US20220072539A1 - Handheld impedance-based diagnostic test system for detecting analytes - Google Patents

Handheld impedance-based diagnostic test system for detecting analytes Download PDF

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Publication number
US20220072539A1
US20220072539A1 US17/416,095 US201917416095A US2022072539A1 US 20220072539 A1 US20220072539 A1 US 20220072539A1 US 201917416095 A US201917416095 A US 201917416095A US 2022072539 A1 US2022072539 A1 US 2022072539A1
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United States
Prior art keywords
cartridge
sample
test
well
electrode
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Pending
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US17/416,095
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English (en)
Inventor
Kyle William Montgomery
Daniel J. Wade
Shad Pierson
Yuh-Min Chiang
Ronald Phillip Chiarello
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Alveo Technologies Inc
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Alveo Technologies Inc
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Priority to US17/416,095 priority Critical patent/US20220072539A1/en
Publication of US20220072539A1 publication Critical patent/US20220072539A1/en
Pending legal-status Critical Current

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Definitions

  • Some embodiments provided herein include embodiments disclosed in Int. App. Pub. No. WO 2016/057422, U.S. 2016/0097740, 2016/0097741, U.S. 2016/0097739, U.S. 2016/0097742, U.S. 2016/0130639; and Int. App. Pub. No. WO 2018/057647 which claims priority to U.S. App No. 62/398,959, U.S. App No. 62/399,047, U.S. App No. 62/398,925, U.S. App No. 62/398,913, U.S. App No. 62/398,955, and U.S. App No. 62/398,965, which are each expressly incorporated by reference in its entirety.
  • the present application is generally directed to systems, methods, and devices for diagnostics for sensing and/or identifying pathogens, genomic materials, proteins, and/or other small molecules or biomarkers.
  • a small, portable, low-power device provides rapid and robust sensing and identification.
  • Such a device may utilize microfluidics, biochemistry, and electronics to detect one or more targets in the field and closer to or at the point of care.
  • an assay cartridge for containing a sample comprising a target agent for detection by a reader device comprises a cartridge body configured to be received by the reader device, and a cap configured to hold the sample carrier containing the sample.
  • the cartridge body includes a test well containing an excitation electrode and a sensing electrode, wherein the test well is configured to contain at least a portion of the sample comprising the target agent undergoing an amplification process; a sample introduction area configured to receive a sample carrier containing the sample; and a fluid path fluidically coupling the sample introduction area to the test well.
  • the cap is further configured to mechanically couple to the cartridge body, wherein mechanically coupling the cap to the cartridge body causes compression of a trapped volume of a fluid to drive at least a portion of the sample through the fluid path into the test well.
  • the sample carrier comprises a capillary tube
  • the cap comprises a retaining well having an interior diameter larger than an exterior diameter of the capillary tube; and a retaining structure disposed within the retaining well and configured to retain the capillary tube at a position spaced from a side interior wall and a rear interior wall of the retaining well to form at least one air channel fluidically coupled to an inner end of the capillary tube.
  • the cartridge body comprises a base and a translucent cover, the translucent cover comprising a planar surface defining one side of at least one of the test well and the fluid path.
  • the cartridge body further comprise a hollow plunger comprising an interior space fluidically coupled to the fluid path of the cartridge body, wherein the cap comprises a plunger receiving well configured to sealingly receive the hollow plunger, and, as the cap is mechanically coupled to the cartridge body, the plunger compresses a volume of air within the plunger receiving well, such that the air flows through the hollow plunger and forces the sample to travel into the fluid path of the cartridge body.
  • the test well is configured to mix a reagent and the sample into a substantially evenly mixed test fluid.
  • the reagent comprises one or more dried reagents stored within the test well.
  • the cartridge body comprises a plurality of test wells, and at least a first test well of the plurality of test wells stores a reagent different from a reagent stored in a second test well of the plurality of test wells.
  • the cartridge body comprises a plurality of test wells, and at least two test wells of the plurality of test wells store the same reagent.
  • the cartridge body further comprises a mixing chamber positioned between the sample introduction area and the test well along the fluid path, the mixing chamber configured to mix a reagent and the sample into a substantially evenly mixed test fluid.
  • the reagent comprises one or more dried reagents stored within the mixing chamber.
  • the assay cartridge further comprises a first electrode interface including a first contact pad leading to the excitation electrode and a second contact pad leading to the sensing electrode.
  • the assay cartridge further comprises a gas-permeable, liquid-impermeable vent fluidically coupled to the test well.
  • the assay cartridge further comprises a machine-readable cartridge identifier printed thereon, the cartridge identifier associated with one or more test protocols.
  • the assay cartridge is a disposable single-use assay cartridge.
  • the trapped volume of a fluid comprises air.
  • the power cartridge includes an internal portion configured to fit within the cavity; and circuitry disposed at least partially on the internal portion and configured to establish an electrical connection with the electrode interface when the power cartridge is inserted into the reader device. Inserting the power cartridge into the cavity causes the reader device to power off, and removing the power cartridge from the cavity causes the reader device to power on.
  • the visual status indicator comprises a ring of lights at least partially surrounding the cavity of the reader device. In some embodiments, the visual status indicator is configured to indicate at least one of a ready status, a testing status, a completed testing status, an error status, and a wireless pairing status.
  • the assay cartridge or system is for use in detecting a target agent.
  • the target agent is a nucleic acid, preferably a nucleic acid of a pathogen.
  • the sample is a biological sample obtained from a subject, such as a human.
  • a method of using the assay cartridge or system for detecting a target agent comprises contacting a biological sample from a subject, preferably a human, with the assay cartridge or system; and detecting the presence of the target agent.
  • the target agent is a nucleic acid, preferably a nucleic acid of a pathogen.
  • the target agent is a nucleic acid and the assay cartridge or system or method further comprises amplifying the nucleic acid, such as by Loop-Mediated Isothermal Amplification (LAMP) and measuring or analyzing a modulation of an electrical signal, such as impedance or capacitance, which is desirably compared to a control.
  • LAMP Loop-Mediated Isothermal Amplification
  • a detection system for detecting a target agent comprises a reader device, an assay cartridge, and a mobile device.
  • the reader devices includes a cavity configured to receive cartridges, a memory storing at least computer-readable instructions, a processor in communication with the memory, a communication interface, and an electrode interface in communication with the processor and electrodes of the cartridges.
  • the sample carrier comprises a capillary tube
  • the cap comprises: a retaining well having an interior diameter larger than an exterior diameter of the capillary tube; and a retaining structure disposed within the retaining well and configured to retain the capillary tube at a position spaced from a side interior wall and a rear interior wall of the retaining well to form at least one air channel fluidically coupled to an inner end of the capillary tube.
  • the cartridge body further comprises a mixing chamber positioned between the sample introduction area and the test well along the fluid path, the mixing chamber configured to mix a reagent and the sample into a substantially evenly mixed test fluid.
  • a detection system for detecting a target agent comprising: a reader device including: a cavity configured to receive cartridges; a memory storing at least computer-readable instructions; a processor in communication with the memory; and an electrode interface in communication with the processor; an assay cartridge including: an external portion; an internal portion configured to fit within the cavity of the reader device, the internal portion including an electrode interface configured to establish an electrical connection with the electrode interface of the reader device when the assay cartridge is inserted into the reader device; and a flow path configured to sealingly enclose a fluid sample within the assay cartridge; and a power cartridge including: an internal portion configured to fit within the cavity; and circuitry disposed at least partially on the internal portion and configured to establish an electrical connection with the electrode interface when the power cartridge is inserted into the reader device, wherein inserting the power cartridge into the cavity causes the reader device to power off, and wherein removing the power cartridge from the cavity causes the reader device to power on.
  • the reader device further includes a communication module configured to connect to a remote computing device executing a user interface application.
  • the visual status indicator is configured to indicate at least one of a ready status, a testing status, a completed testing status, an error status, and a wireless pairing status.
  • a method of using the assay cartridge or system of any one of alternatives 1-31 for detecting a target agent comprising: contacting a biological sample from a subject, preferably a human, with the assay cartridge or system of any one of claims 1 - 30 ; and detecting the presence of the target agent.
  • LAMP Loop-Mediated Isothermal Amplification
  • test well further contains a third electrode.
  • An assay cartridge for analyzing a sample comprising a target agent comprising: a cartridge body configured to be received by a reader device, the cartridge body including: at least one test well containing an excitation electrode and a sensing electrode, wherein the at least one test well is configured to contain at least a portion of the sample comprising the target agent undergoing an amplification process; a sample introduction area configured to receive a sample carrier containing the sample; and a fluid path fluidically coupling the sample introduction area to the test well; and a reagent blister configured to hold a reagent to be mixed with the sample prior to the amplification process, the reagent blister further configured to be ruptured when the cartridge body is inserted into the reader device, wherein the rupturing of the reagent blister produces a force that mixes the reagent with the sample and drives at least a portion of the reagent and at least the portion of the sample through the fluid path to the at least one test well.
  • a detection system for detecting a target agent comprising: a reader device including: a cavity configured to receive cartridges; a memory storing at least computer-readable instructions; a processor in communication with the memory; a communication interface; and an electrode interface in communication with the processor and electrodes of the cartridges; an assay cartridge including: an external portion; an internal portion configured to fit within the cavity of the reader device, the internal portion including electrodes configured to establish an electrical connection with the electrode interface of the reader device when the assay cartridge is inserted into the reader device; a flow path configured to fluidically couple a sample introduction area of the assay cartridge to at least one test well of the assay cartridge; and a reagent store configured to store a reagent for mixing with a sample prior to conveying at least a portion of a mixture of the reagent and the sample to the at least one test well; and a mobile device including: a data store storing at least computer-readable instructions for the mobile device; a hardware processor in communication with the memory; an interface for identifying a
  • each of the one or more symptoms has associated therewith a sliding scale value representative of a severity of the symptom.
  • the mobile device is further configured to display, to the user, information from the reader device, the information comprising a time remaining before the test results are generated, an identifier of the reader device, and an identifier of the assay cartridge.
  • the mobile device is further configured to display, to the user, test results for the sample, any symptoms associated with the sample, an indication of the diagnosed ailment, and one or more of a recommended follow-up steps for the diagnosed ailment.
  • alert comprises one or more of a phone call, a text message, an e-mail message, a push message, an audio message, a flashing indicator, or audible indicator.
  • the aggregating device is further configured to automatically generate a request to vaccine and/or medication suppliers to increase the quantity of available vaccines or medications when insufficient vaccines or medications are available.
  • FIG. 5D depicts the resistance and reactance components extracted from signals as shown in FIG. 5B from example tests of positive and negative controls.
  • FIG. 5E depicts the resistance and reactance components extracted from a signal as shown in FIG. 5B generated based on another example positive test.
  • FIG. 6 depicts a schematic block diagram of an example reader device that can be used with the cartridges described herein.
  • FIG. 7A depicts a flowchart of an example process for operating a reader device during a test as described herein.
  • FIG. 7B depicts a flowchart of an example process for analyzing test data to detect a target as described herein.
  • FIGS. 8A-8D depict an example user interface of a user device implementing an example testing process in communication with a reader device as described herein.
  • FIGS. 9A and 9B depict an example handheld system for detection of a target.
  • FIGS. 10A-10K depict an example cartridge for detection of a target that can be used in the handheld system of FIGS. 9A and 9B .
  • FIGS. 12A-12I depict an example cartridge for detection of a target that can be used in conjunction with the handheld systems disclosed herein.
  • FIGS. 13A-13E depict an example of another type or format of cartridge configured to detect a target that can be used in conjunction with a handheld system disclosed herein.
  • FIGS. 14A and 14B depict an example of another handheld system disclosed herein.
  • a hurdle to point of care (“POC”) testing is the potential inhibition of amplification by interferents often encountered in crude, unprocessed clinical samples such as whole blood, saliva, mucus, or any other bodily fluid or biological component.
  • the mitigation of amplification inhibitors may challenge the direct detection of target nucleic acids from clinically relevant biologic samples.
  • a sample may comprise one or more of blood, saliva, mucus, or any other bodily fluid or biological secretion or component.
  • a high-frequency alternating current (“AC”) signal is applied to the excitation electrode. This signal is capacitively coupled through the solution where it is detected at the signal electrode. By comparing the excitation signal with the signal at the signal electrode, the solution's conductivity can be determined.
  • AC alternating current
  • the parameters corresponding to optimal detection can be interdependent variables. According to the following equation, the measured impedance is a function of the solution resistance, capacitance and the applied frequency:
  • the optimal AC frequency with which to measure solution conductivity by fC 4 D therefore can be chosen with respect to the capacitance of the passivation layer.
  • a system for detecting a target in a sample includes a removable fluidics cartridge that is couplable to a companion reader device.
  • a user can apply a sample to the cartridge and then insert it into the reader device.
  • the reader device is configured for performing the testing procedures using the cartridge and analyzing the test data to determine the presence, absence, or quantity of a target in the sample.
  • the cartridge can be provided with the desired agents, proteins, or other chemical matter for an amplification process by which a target initially present in the sample is amplified.
  • some cartridges can be provided with the desired chemical matter for nucleic acid testing, wherein genomic material in the sample is exponentially copied using a molecular amplification process, as described herein.
  • the cartridge can also include a test well for containing the amplification process, where a test well refers to a well, chamber, channel, or other geometry configured for containing (or substantially containing) test fluid and constituents of the amplification process.
  • the reader device may maintain a desired temperature or other test environment parameters for the cartridge to facilitate the amplification process, and can electronically monitor a test well of the cartridge throughout some or all of the amplification process.
  • the reader device can thus gather signal data representing the impedance of the test well over time during the amplification process, and can analyze the impedance as described herein to ascertain the presence, absence, or quantity of the target in the sample.
  • the amplification process can range from five minutes to sixty minutes, with some examples ranging from ten minutes to thirty minutes.
  • the amplification products are detected while being suspended in the fluid within the wells such that the amplification products are not attached or sequestered to the wells or fixed or bound to probes, which are bound to the wells.
  • the amplification products are detected as they are attached or sequestered to the wells e.g., fixed or bound to probes, which are bound to the wells.
  • Such systems can beneficially provide target detection performable in a clinical setting or even the home of a user, rather than requiring the sample to be sent to a laboratory for amplification and analysis. In the clinical setting, this can avoid the delays of conventional nucleic acid testing thereby enabling clinicians to determine diagnoses within the typical timeframe of a patient's office visit.
  • the disclosed systems enable clinicians to develop treatment plans for patients during their initial office visit, rather than requiring the clinician to wait for hours or even days to receive test results back from a laboratory. For example, when a patient visits a clinic a nurse or other healthcare practitioner can collect a sample from the patient and begin testing using the described system. The system can provide the test result by the time the patient consults with their doctor or clinician to determine a treatment plan. Particularly when used to diagnose pathologies that progress quickly, the disclosed systems can avoid the delays associated with laboratory testing that can negatively impact the treatment and outcome of the patient.
  • the disclosed systems can be used outside of the clinical setting (e.g., in the field, in rural settings without easy access to an established healthcare clinic) to detect health conditions such as contagious diseases (e.g., Ebola), thus enabling the appropriate personnel to take immediate action to prevent or mitigate the spread of a contagious disease.
  • the disclosed systems can be used in the field or at the site of a suspected hazardous contaminant (e.g., anthrax) to quickly determine whether a sample contains the hazardous contaminant, thus enabling the appropriate personnel to take immediate action to prevent or mitigate human exposure to the contaminant.
  • the disclosed systems can be used to detect contaminants in the blood or plasma supply or in the food industry. It will be appreciated that the disclosed systems can provide similar benefits in other scenarios in which real-time detection of a target enables more effective action than delayed detection through sending a sample to an off-site laboratory.
  • a single use cartridge includes a cartridge body and a cap which, when mechanically coupled together, create pressurized air that propels a collected sample from the cap into a mixing well and a test well of the cartridge body, reducing a necessary level of skill required to operate the reader device and reducing the complexity of both the cartridge and the reader device.
  • FIGS. 1A-1C depict an example handheld detection system 100 for detection of a target.
  • the system 100 includes a reader device 110 and a cartridge 120 configured to fit within a cavity 112 of the reader device 110 .
  • the cartridge 120 generally includes an external section 122 and an internal section 124 . When the cartridge 120 is inserted within the reader device 110 , some or all of the internal section 124 is contained within the reader device 110 .
  • the external section 122 is sized and shaped to be gripped by a user and may include one or more three-dimensional surface features such as an indentation 126 to facilitate insertion and/or removal of the cartridge 120 from the reader device 110 .
  • the reader device 110 and the cartridge 120 are sized and shaped such that one or more interchangeable cartridges 120 can be inserted and/or removed by hand at the cavity 112 .
  • the reader device 110 can include one or more heating components configured to heat at least a portion of the internal section 124 of the cartridge 120 .
  • the reader device 110 can further include circuitry configured to connect with circuitry of the cartridge 120 to detect one or more electrical properties of a sample contained within the cartridge.
  • the circuitry of the power cartridge 120 again comes into contact with the internal circuitry of the reader device 110 such that insertion of the power cartridge 120 causes the reader device 110 to power off. Power cartridge applications are discussed in greater detail with reference to FIG. 6 .
  • one or more external status indicators can be provided on an exterior portion of the reader device 110 to provide status indications to a user.
  • the status indicator may include a light ring 114 disposed about the cavity 112 .
  • the optional status indicators may be located at any suitable location on the reader device 110 .
  • the light ring 114 or other status indicator may include one or more light sources, such as light emitting diodes (LEDs) or the like.
  • the light ring may also be configured to indicate e.g., when the device is in use or not in use, or when different stages of the detection method using the device have been reached, completed, or are being performed, such as sample being received by the device or in the well(s), amplification being performed, detection of aggregates in the well(s), or transmission of the results to a receiver.
  • Different colored lights can be used to indicate different stages of the detection method using the device such as those mentioned above.
  • Each light source may be operated in a number of modes, such as a “solid” mode characterized by continuous activation of the light source (e.g., a steady “on” state), a “blinking” mode characterized by repeated activation and deactivation of the light source, a “flash” mode characterized by a single activation and deactivation of the light source, a “breathing” mode characterized by repeated gradual brightening and dimming of the light source, etc.
  • a “solid” mode characterized by continuous activation of the light source (e.g., a steady “on” state)
  • a “blinking” mode characterized by repeated activation and deactivation of the light source
  • flash flash
  • a “breathing” mode characterized by repeated gradual brightening and dimming of the light source
  • FIGS. 2A and 2B depict a complete cartridge 200 including the cartridge body 210 and the cap 240 coupled together.
  • the cap 240 and cartridge body 210 can operate to seal a provided sample within the cartridge 200 , thereby preventing exposure of test operators to the sample and preventing any liquid from escaping into the electronics of an associated reader device.
  • the cartridge body 210 and the cap 240 may be coupled by a friction fit, a snap fit, and/or one or more mechanical or chemical securing means. Coupling of the cartridge body 210 and the cap 240 is discussed in greater detail with reference to FIGS. 3A-3E .
  • the cartridge identifier 215 can include any suitable information associated with the cartridge, such as information specifying a type of test, a target agent, a sample type, a cartridge serial number or other individual cartridge identifier, etc.
  • the cartridge identifier 215 may also be scanned by a user (e.g., using a user interface device in communication with a reader device) to communicate one or more test protocols to the reader device.
  • the cartridge body 210 and/or the cap 240 can include ergonomic features such as an indentation 216 to facilitate handling of the cartridge 200 .
  • FIGS. 2C and 2D depict the cartridge body 210 component of the cartridge 200 of FIGS. 2A and 2B .
  • the cartridge body 210 includes a base 211 and a cover 212 .
  • the base 211 can be formed from a fluid-impermeable material, for example injection molded or milled acrylic or plastic.
  • the base 211 includes a receiving well 218 and components of a cartridge body flow path, including a first segment 222 , a mixing well 224 , a second segment 226 , a test well 228 , a third segment 230 , and a vent 232 . It will be appreciated that the particular geometric configurations or relative arrangements of these features may be varied in other embodiments.
  • fluidic communication refers to the capability to transfer fluids (e.g., liquid or gas).
  • the cover 212 can be formed from a fluid-impermeable material.
  • the cover 212 is a translucent or transparent material, such as glass, plastic, or the like.
  • the cover 212 is sealed to the base 211 to form the cartridge body 210 and to serve as a boundary confining fluids within the cartridge body flow path components described above.
  • a translucent or transparent cover 212 advantageously allows for visual inspection of a fluid within the cartridge body flow path (e.g., to verify that the test well is full prior to testing, etc.).
  • One or more conductive components of an electrode interface 214 are disposed on the cover 212 .
  • Mating features 238 are sized and shaped to receive corresponding mating features of the cap 240 .
  • the receiving well 218 optionally includes a chamfer 220 to facilitate coupling of the cap 240 to the cartridge body 210 .
  • the mixing well 224 may include one or more reagents in a dry form (e.g., a powder). Powdered reagents and/or other dry reagents may be hydrated by a fluid sample when the fluid sample enters the mixing well 224 .
  • the reagents provided in the mixing well 224 can be selected based on one or more protocols of the intended test associated with the cartridge 200 . Even or homogenous mixing of the reagents with the fluid sample can yield more accurate test results in some embodiments.
  • the mixing well 224 is configured to promote even mixing of the reagent with the fluid sample, for example by including curved regions and/or a cross-sectional shape that promote turbulent flow rather than laminar flow of the liquids within the mixing well 224 .
  • Turbulent flow is a flow regime in fluid dynamics characterized by chaotic changes in pressure and flow velocity of a fluid. Turbulent flow is in contrast to laminar flow, which occurs when fluid flows in parallel layers, with no disruption between those layers.
  • the segments 222 , 226 , and 230 of the cartridge body flow path, the mixing well 224 , and/or the test well 228 can be entirely encased within the material of the base 211 , or can have three surfaces formed from the material of the base 211 with the cover 212 forming an upper surface that seals these channels.
  • the mixing well 224 can be provided with solid dried or lyophilized constituents for the testing process, for example primers and proteins.
  • the particular selection and chemistry of these dried or lyophilized constituents can be tailored to a particular target or targets for which the cartridge 200 is designed to test.
  • These dried or lyophilized constituents can be hydrated with the liquid e.g., a buffer or liquid sample that flows into the test well (e.g., the fluid sample within the cartridge 200 ) and thus activated for the test procedure.
  • a buffer or liquid sample that flows into the test well (e.g., the fluid sample within the cartridge 200 ) and thus activated for the test procedure.
  • providing the dried or lyophilized solid constituents in the mixing well 224 enables the cartridge 200 to be stored before use containing the components needed for the amplification process, while also delaying initiation of amplification until after the sample has been applied.
  • the test well 224 is depicted as a generally cylindrical well formed as a circular opening in the material of the base 211 and bounded by the planar surface of the cover 212 .
  • the test well 224 contains two electrodes 213 , 215 , with one electrode being an excitation electrode configured to apply current to the sample in the test well 224 and the other electrode being a signal electrode configured to detect current flowing from the excitation electrode through the liquid sample.
  • one or more test wells can be provided with a thermistor in place of the electrodes in order to provide for monitoring of the temperature of the fluid within the cartridge 100 .
  • the electrodes 213 , 215 may be positioned at the bottom of the test well 224 in some embodiments. This can allow any air or gas to rise to the top of the fluid in the test well and away from the path between the electrodes.
  • the bottom of the test well 224 refers to the portion of the test well in which heavier liquid settles due to gravity
  • the top of the test well refers to the portion of the test well in which lighter gas rises above the heavier liquids.
  • the electrodes 213 , 215 are positioned away from the perimeter or edges of the test well 224 which is a location at which bubble nucleation typically occurs.
  • the electrodes 213 , 215 can be formed from a thin, flat layer of material that has minimal height relative to the underlying circuit board layer that forms the bottom of the test well 224 .
  • the electrodes 213 , 215 can be formed using electrodeposition and patterning to form a thin layer of metal film, for example around 300 nm in height. This minimal height can help prevent or mitigate air bubbles from becoming trapped along the interface between the electrode and the underlying layer.
  • a layer of conductive material can be deposited on top of each electrodes to create a smoother transition between the edge of the electrode and the bottom of the test well.
  • a thin polymid layer e.g., around 5 microns in height
  • the electrodes can be positioned in grooves in the underlying layer with the grooves having a depth approximately equal to the height of the electrode.
  • FIGS. 2E and 2F depict the cap 240 component of the cartridge 200 .
  • FIG. 2F is a cross-sectional view taken about the line 2 F- 2 F in FIG. 2E to illustrate internal structures of the cap 240 .
  • the cap 240 is sized and shaped to mate with or otherwise mechanically couple to the cartridge body 210 to form a complete cartridge 200 .
  • the cap 240 includes mating features 242 configured to interlock with corresponding mating features 238 of the cartridge body when the cartridge 200 is assembled.
  • the cap further includes a plunger 244 disposed about a retaining well 250 for retaining a capillary tube therein.
  • the plunger 244 is sized and shaped to sealingly engage with the receiving well 218 of the cartridge body 210 ( FIGS. 2C-2D ).
  • the plunger 244 optionally includes a groove 246 configured to receive an O-ring or other gasket to eve and/or enhance the seal between the plunger 244 and the receiving well 218 .
  • An optional chamfer 248 at a distal end of the plunger 244 may facilitate the engagement of the plunger 244 with the receiving well 218 , alone or in combination with the chamfer 200 of the receiving well 218 ( FIGS. 2C-2D ).
  • the plunger 244 thus sealingly engages with the receiving well 218 to propel a fluid sample into the cartridge body 210 .
  • the retaining well 250 is configured to partially surround a capillary tube containing a fluid sample for testing.
  • the retaining well 250 preferably has an interior diameter larger than the exterior diameter of the capillary tube to be inserted.
  • a plurality of retaining structures 252 extend inward from the interior walls of the retaining well 250 to hold the capillary tube at a central location within the retaining well 250 .
  • the distance between opposing retaining structures 252 is approximately equal to or slightly larger than the exterior diameter of the capillary tube.
  • a rear portion 254 of each retaining structure 252 extends further inward relative to the remaining portion of the retaining structure 252 .
  • the cartridge 200 of FIGS. 2A-2F provides a self-contained, easy to use device for performing an amplification-based test for a target, for example nucleic acid testing wherein genomic material in the sample is exponentially copied using a molecular amplification process.
  • the user only needs to apply the sample and insert the cartridge 200 into a reader device in order to ascertain the result of the test in some embodiments, as the solid constituents of the amplification process are pre-provided within the cartridge and automatically mixed with the sample.
  • one or both of the cartridge or reader may include a heater and a controller configured to operate the heater to maintain the cartridge at the desired temperature for amplification.
  • one or both of the cartridge or reader may include a motor to impart vibrations to or otherwise agitate the cartridge to cause any trapped gas to rise to the top of the liquid and vent from the test wells.
  • FIGS. 3A-3E illustrate mechanical fluid transfer aspects of the cartridges 120 , 200 described herein.
  • the cartridge body 210 and cap 240 are configured to create air pressure when coupled together, such that the air pressure propels a fluid sample through the fluid path of the cartridge body 210 .
  • the fluid sample may be driven through the fluid path of the cartridge body 210 by capillary action or wicking, instead of or in addition to fluid pressure.
  • FIGS. 3A-3E illustrate the cap 240 with translucency to reveal interior features of the cap 240 .
  • the cartridge body 210 is illustrated in a cutaway view in FIGS. 3C-3E to reveal interior features of the cartridge body 210 .
  • a fluid sample may be received in a capillary tube 300 , for example, within an inner lumen 305 of the capillary tube 300 .
  • the cap 240 is sized and shaped to receive the capillary tube 300 as described above with reference to FIGS. 2E and 2F .
  • the fluid sample may be introduced into the capillary tube 300 while the capillary tube 300 is within the cap 240 , or the capillary tube 300 may contain the fluid sample when it is placed into the cap 240 .
  • FIG. 3A is a front view of the cap 240 of the cartridge 200 . While the capillary tube 300 is disposed within the retaining well 250 of the cap 240 , the retaining structures 252 hold the capillary tube 300 in a position spaced from the walls of the retaining well 250 . Thus, a plurality of air channels 310 are formed between the interior of the retaining well 250 and the exterior of the capillary tube 300 .
  • FIG. 3B is a top view of the cap 240 of FIG. 3A .
  • a rear portion 310 of some or all of the retaining structures 310 e.g., the rear portions 254 of FIG. 2F ) cause the capillary tube 300 to remain spaced from the rear of the retaining well 250 .
  • This arrangement forms a cap fluid path 315 such that air or other fluids can flow into the retaining well 250 through the air channels 310 , around the rear of the capillary tube 300 , and out of the retaining well 250 through the inner lumen 305 of the capillary tube 300 .
  • application of a relatively high pressure at the air channels 310 can cause a fluid within the inner lumen 305 to flow out of the capillary tube 300 along the cap fluid path 315 .
  • the plunger 244 , retaining well 250 , and capillary tube 300 are aligned with the receiving well 218 of the cartridge body 210 .
  • the plunger 244 is sized and shaped to sealingly engage the receiving well 218 .
  • An O-ring or other seal (not shown) can be positioned in the groove 246 of the plunger 244 to achieve and/or enhance the seal between the plunger 244 and the receiving well 218 .
  • the receiving well 218 is fluidically coupled to the mixing well 224 by an inlet 221 sized and shaped to sealingly receive an end of the capillary tube 300 .
  • the plunger 244 engages the walls of the receiving well 218 .
  • a volume of ambient air is trapped within the receiving well 218 .
  • This trapped air 320 has a volume defined by the portion of the receiving well 218 not occupied by the plunger 244 .
  • the trapped air 320 is compressed within the shrinking volume of the portion of the receiving well 218 not occupied by the plunger 214 . Because the inlet 221 is blocked by the capillary tube 300 , the compression of the trapped air 320 causes the trapped air 320 to flow along the cap flow path 315 of FIG. 3B .
  • FIG. 3E illustrates the flow along the cap flow path 315 and the cartridge body flow path 325 with encircled numbers shown as labels for certain points along the fluid path.
  • the encircled numbers are discussed below as example steps of a progression of trapped air 320 and a fluid sample as they travel through the cap flow path 315 and the cartridge body flow path 325 within the cartridge 200 , with each step including a directional arrow showing the direction of fluid travel at that step.
  • some components labeled with reference numbers in FIGS. 2A-3D are not labeled in FIG. 3E .
  • a user Prior to step (1), a user provides a fluid sample within a capillary tube 300 . Also prior to step (1), the capillary tube 300 is placed within the retaining well 250 of the cap 240 between the retaining structures 252 to form the cap flow path 315 .
  • step (1) as the plunger 244 compresses the trapped air 320 , the trapped air 320 is forced into the air channels 310 .
  • the trapped air 320 flows along the cap flow path 315 through the air channels 310 between the retaining structures 252 and along the exterior of the capillary tube 300 .
  • the trapped air 320 reaches the rear of the retaining well 218 .
  • the trapped air 320 continues along the cap flow path 315 into the inner lumen 305 of the capillary tube 300 .
  • the trapped air 320 contacts and exerts a pressure upon the fluid sample contained within the capillary tube 300 .
  • the pressure is directed along the length of the capillary tube 300 toward the cartridge body 210 .
  • the fluid sample flows out of the capillary tube 300 and into the inlet 221 of the cartridge body 210 .
  • the fluid sample is propelled into the inlet 221 by the pressured exerted at the opposite end of the capillary tube 300 by the trapped air 320 .
  • Capillary action or wicking may also propel the fluid sample into the inlet 221 , for example, where the inlet and fluidically connected segments along the cartridge body flow path 325 are suitably narrow to cause wicking.
  • the fluid sample travels through the first segment 222 of the cartridge body flow path 325 .
  • the fluid sample enters the mixing well 224 .
  • the mixing well may include one or more reagents. Agitation caused by the flow of the fluid sample within the relatively larger space of the mixing well 224 causes the reagent and the sample to be mixed.
  • the reagent and the fluid sample are mixed into a homogeneous solution in which the reagent is evenly distributed throughout the fluid sample.
  • the depth, width, and/or cross-sectional profile of the mixing well 224 may be selected to facilitate mixing of the reagent and the fluid sample.
  • the mixed reagent and fluid sample (referred to as the “test fluid”) leave the mixing well 224 and travel along the second segment 226 of the cartridge body flow path 325 into the test well 228 .
  • a portion of the test fluid continues along the third segment 230 of the cartridge body flow path 325 to fill any remaining open volume within the cartridge body flow path 325 .
  • the path of step (7) shows the optional flow of a gas (e.g., a gas portion of the test fluid or ambient air present within the cartridge body 210 ) through the valve 232 .
  • the valve 232 can include a liquid-impermeable, gas-permeable filter to allow any gas present in the test fluid or within the cartridge body 210 to vent through the valve 232 as the test fluid fills the space within the cartridge body flow path 325 .
  • the valve 232 may further minimize the occurrence of air bubbles within the test well 228 .
  • the valve 232 may not present and/or may not be configured to vent gas.
  • the illustrated electrodes of FIGS. 4A-4N can be rotated in other implementations.
  • the disclosed example dimensions represent certain potential implementations of the electrode configurations 400 A- 400 G, and variations can have different dimensions that follow the same ratios between the provided example dimensions.
  • the electrodes shown in FIGS. 4A-4N can be made from suitable materials including platinum, gold, steel, or tin. In experimental testing, tin and platinum performed similarly and suitably for certain test setups and test targets.
  • FIG. 4A depicts a first electrode configuration 400 A wherein the first and second electrodes 405 A, 405 B are each formed as a semicircular perimeter.
  • the straight edge of the first electrode 405 A is positioned adjacent to the straight edge of the second electrode 405 B and separated by a gap along the width of the configuration 400 A.
  • the gap is larger than the radius of the semicircle of the electrodes.
  • the first and second electrodes 405 A, 405 B are positioned as mirrored semicircular perimeters.
  • FIG. 4B depicts a second electrode configuration 400 B. Similar to the first electrode configuration 400 A, the first and second electrodes 410 A, 410 B of the second electrode configuration 400 B are each formed as a semicircular perimeter and are positioned as mirrored semicircles with their straight edges facing one another. The first and second electrodes 410 A, 410 B of the second electrode configuration 400 B can be the same size as the first and second electrodes 405 A, 405 B of the first configuration 400 A. In the second electrode configuration 400 B, the gap along the width of the configuration 400 B between the first and second electrodes 410 A, 410 B is smaller than in the first configuration 400 A, and the gap is smaller than the radius of the semicircle of the electrodes 410 A, 410 B.
  • the gap between the closest portions of the first and second electrodes 410 A, 410 B spans approximately 10.158 mm
  • the height (along the straight edge) of each of the electrodes 410 A, 410 B is approximately 25.399 mm
  • the radius of the semicircle of each of the electrodes 410 A, 410 B is approximately 12.703 mm.
  • the gap between the closest portions of the first and second electrodes 425 A, 425 B spans approximately 25.399 mm
  • the height of each of the electrodes 425 A, 425 B is also approximately 25.399 mm
  • the width of each of the electrodes 425 A, 425 B is approximately 5.078 mm.
  • the ends of the first and second electrodes 425 A, 425 B can be radiused, for example having a radius of around 2.542 mm.
  • FIG. 4F depicts a sixth electrode configuration 400 F having concentric annular electrodes 430 A, 430 B.
  • the sixth electrode configuration 400 F is the configuration shown in the test well 228 of FIGS. 2A, 2C, and 2D .
  • the inner electrode 430 B can be a disc or circular-shaped electrode and can be positioned in the center of the test well.
  • the outer electrode 430 A can be a semicircular electrode formed concentrically around the inner electrode 430 B and separated from the inner electrode 430 B by a gap. In the sixth electrode configuration 400 F, the gap is approximately equal to the radius of the inner electrode 430 B.
  • a break in the semicircle of the outer electrode 430 A occurs where a conductive lead connects the inner electrode 430 B to the current providing conductor.
  • the gap between the inner edge of the annular first electrode 430 A and the outer perimeter of the circular second electrode 430 B spans approximately 11.430 mm
  • the radius of the circular second electrode 430 B is approximately 17.777 mm
  • the thickness of the annulus of the annular first electrode 430 A is approximately 5.080 mm.
  • the ends of the first electrode 430 A can be radiused, for example having a radius of around 2.555 mm, and the gap between the open ends of the annulus of the first electrode 435 A can be around 28.886 mm from vertex to vertex.
  • FIG. 4G depicts a seventh electrode configuration 400 G having concentric annular electrodes 435 A, 435 B.
  • the inner electrode 435 B can be a disc or circular-shaped electrode having the same radius as inner electrode 430 B and can be positioned in the center of the test well.
  • the outer electrode 435 A can be a semicircular electrode formed concentrically around the inner electrode 435 A and separated from the inner electrode 435 A by a gap.
  • the gap is greater than the radius of the inner electrode 435 B, for example two to three times greater.
  • the outer electrode 435 B has a larger radius than the outer electrode 430 B.
  • either electrode can be used as the excitation electrode and the other electrode can be used as the signal electrode.
  • the inner electrode 430 B, 435 B is configured to be used as the excitation electrode (e.g., coupled to a current source) and the outer electrode 430 A, 435 A is configured to be used as the signal electrode (e.g., provides its signal to a memory or processor).
  • the sixth electrode configuration 400 F exhibited the best performance of the configurations shown in FIGS. 4A-4G .
  • FIGS. 4H-4N depict further examples of electrode configurations suitable for implementing three-terminal sensing and/or four-terminal sensing.
  • three-terminal sensing e.g., potentiostat-type or 3-wire measurement
  • four-terminal sensing e.g., Kelvin-type or 4-wire measurement
  • the excitation electrode and the signal electrode may themselves carry some charge.
  • a third electrode or a third and fourth electrode e.g., a second electrode pair
  • the third and/or fourth electrodes can carry a substantially smaller or negligible current relative to the current carried by the excitation and signal electrodes.
  • the third and/or fourth electrodes may thus be used to accurately determine a voltage (e.g., a voltage between the third and fourth electrodes, or a voltage between the third electrode and the excitation or signal electrode). This precisely measured voltage may be used to determine an impedance measurement having enhanced accuracy.
  • a voltage e.g., a voltage between the third and fourth electrodes, or a voltage between the third electrode and the excitation or signal electrode.
  • This precisely measured voltage may be used to determine an impedance measurement having enhanced accuracy.
  • FIGS. 4H-4N are merely examples of a number of three- or four-terminal configurations that may be provided within the test wells of the present disclosure.
  • FIG. 4H depicts an electrode configuration similar to the electrode configuration of FIG. 4A , with the addition of a third electrode 440 A and a fourth electrode 440 B disposed between the first electrode 405 A and the second electrode 405 B. Either or both of the third electrode 440 A and the fourth electrode 440 B may be used to implement three- or four-terminal sensing.
  • FIG. 4I depicts an electrode configuration similar to the electrode configuration of FIG. 4B , with the addition of a third electrode 440 A disposed between the first electrode 410 A and the second electrode 410 B.
  • the third electrode 440 A may be used to implement three-terminal sensing.
  • FIG. 4J depicts an electrode configuration similar to the electrode configuration of FIG. 4C , with the addition of a third electrode 440 A and a fourth electrode 440 B disposed between the first electrode 415 A and the second electrode 415 B. Either or both of the third electrode 440 A and the fourth electrode 440 B may be used to implement three- or four-terminal sensing.
  • FIG. 4K depicts an electrode configuration similar to the electrode configuration of FIG. 4D , with the addition of a third electrode 440 A disposed between the first electrode 420 A and the second electrode 420 B.
  • the third electrode 440 A may be used to implement three-terminal sensing.
  • FIG. 4L depicts an electrode configuration similar to the electrode configuration of FIG. 4E , with the addition of a third electrode 440 A disposed between the first electrode 425 A and the second electrode 425 B.
  • the third electrode 440 A may be used to implement three-terminal sensing.
  • FIG. 4M depicts an electrode configuration similar to the electrode configuration of FIG. 4F , with the addition of a third electrode 440 A disposed between the outer electrode 430 A and the inner electrode 430 B.
  • the third electrode 440 A may be used to implement three-terminal sensing.
  • FIG. 4N depicts an electrode configuration similar to the electrode configuration of FIG. 4G , with the addition of a third electrode 440 A and a fourth electrode 440 B disposed between the outer electrode 435 A and the inner electrode 435 B. Either or both of the third electrode 440 A and the fourth electrode 440 B may be used to implement three- or four-terminal sensing.
  • FIG. 5A schematically depicts a first electrode or excitation electrode and a second electrode or signal electrode that may be spaced apart from one another within a test well of the cartridges of FIGS. 2A-3E or in the test well or channel of another suitable target detection cartridge as described herein.
  • the attenuated excitation voltage is sensed or detected at the sensing electrode 510 B.
  • the fluid acts as a resistor R in series with the excitation electrode 510 A and the sensing electrode 510 B.
  • the fluid also acts as in series capacitor(s), shown by the reactance X.
  • the raw sensed signal during some or all of the duration of a test can be represented over time as a sinusoidal curve with varying amplitudes, similar to that shown in plot 520 .
  • the sensor drive frequency can be similarly fine-tuned for other tests to optimize performance, that is, to optimize the detectability of a signal cliff. Detectability of a signal cliff refers to the ability to consistently differentiate between a positive sample and a negative sample.
  • FIG. 5B depicts an example plot 525 showing an impedance signal 530 that can be extracted from the raw signal 520 provided by the sensing electrode 510 B.
  • the impedance signal 530 represents the electrical impedance Z of the test well over time.
  • the impedance Z can be represented by a Cartesian complex number equation as follows:
  • R represents the resistance of the test well and is the real part of the above equation
  • X represents the reactance of the test well and is the imaginary part of the above equation (denoted by j).
  • the value of the resistance R can be determined by taking a baseline measurement of the test well prior to or at the outset of the amplification process. Although the resistance of the test fluid can drift away from this baseline value throughout the duration of the test, the current sensed by the sensing electrode 510 B due to the resistance of the test fluid can be in phase with the signal provided through the excitation electrode 510 A. Thus, changes or drift in the resistance can be identified by values of the in phase component of the signal 520 over time.
  • the reactance can arise from the effect of inductance in the test fluid, capacitance in the test fluid, or both; this effect can cause the fluid to retain current (e.g., electrons provided by excitation electrode 510 A) temporarily.
  • the current sensed by the sensing electrode 510 B due to the reactance of the test fluid can be out of phase with the current sensed from the resistance of the test fluid.
  • values of the reactance of the test fluid can be identified by values of the out of phase component of the signal 520 over time.
  • the reactance can fluctuate throughout the duration of the test based on changes to the chemical constituents of the test fluid due to the amplification process.
  • the signal cliff e.g., a rise or drop in the reactance at or greater than a threshold rate or magnitude and/or during a predetermined window of time
  • indicative of a positive sample can be found in the reactance X.
  • the magnitude of the change AR in the reactance that corresponds to a positive sample signal cliff 545 can vary depending on a number of parameters of the test. These parameters include the particular target of the test (e.g., the rate at which that target amplifies), the frequency of the excitation voltage, the configuration of the excitation and sensor electrodes (e.g., their individual shapes and dimensions, the gap separating the electrodes, and the material of the electrodes), the sampling rate, the quantity of amplification agents provided at the start of the test, the temperature of the amplification process, and the amount of target present in the sample.
  • the particular target of the test e.g., the rate at which that target amplifies
  • the frequency of the excitation voltage e.g., the configuration of the excitation and sensor electrodes (e.g., their individual shapes and dimensions, the gap separating the electrodes, and the material of the electrodes)
  • the sampling rate e.g., their individual shapes and dimensions, the gap separating the electrodes, and the material of the electrodes
  • the expected characteristics of a signal cliff of a positive sample can be used for differentiating between positive samples and negative samples.
  • the expected characteristics of a signal cliff can be used for determining the severity or progress of a medical condition, for example via correlations between particular signal cliff characteristics and particular initial quantities of the target in the sample.
  • the predetermined expected characteristics can be provided to, stored by, and then accessed during test result determination by a reader device configured to receive signals from the sensing electrode(s) of a test cartridge.
  • the test fluid initially included amplification primers and 1,000,000 added target copies
  • the excitation voltage was 200 mV P2P
  • the test parameters included a 10 kHz sweep start and a 10 MHz sweep stop for the frequency of the excitation current
  • close and far electrode gaps were configured at 2.55 mm and 5 mm respectively.
  • the amplification temperature was set to 65.5 degrees Celsius
  • the two electrode setups (one for each of the close and far gaps) included platinum electrodes.
  • a test well in a test cartridge may be configured with the 5 mm gap electrodes and a reader device may be configured to provide 10 kHz excitation current to the test cartridge during amplification.
  • the reader device can be provided with instructions to provide this current and monitor the resulting reactance of the test well throughout amplification or for a window of time around the expected signal cliff time (here, 23 minutes), for example between 20 and 35 minutes.
  • the reader device can also be provided with instructions to identify a positive sample based on the reactance exhibiting around a 3.5-4 Ohm change around 23 minutes into amplification, or within the window of time around the expected signal cliff time.
  • the values for AR and Tw can be provided to reader devices for use in distinguishing between positive and negative samples for that particular test.
  • such devices can determine whether the reactance curve 540 B has the required value and/or slope at the identified window of time Tw to correspond to the signal cliff.
  • the reader device can analyze the shape of the reactance curve over time to determine whether it contains a signal cliff.
  • a reader can modify its testing procedures based on the identified window of time Tw at which the signal cliff 545 is expected to occur, for example by only providing the excitation voltage and monitoring the resultant signal within this window, advantageously conserving power and processing resources compared to continuous monitoring during an entire test time.
  • FIG. 5D depicts a plot 551 of the resistance and reactance components extracted from the raw sensor data of a sensing electrode 510 B during example tests of positive and negative controls.
  • the plot 551 shows a curve 550 A of the resistance of the positive sample, a curve 550 B of the reactance of the positive sample, a curve 550 C of the resistance of the positive sample, and a curve 550 D of the reactance of the positive sample over the 35 minute duration of the test.
  • the positive sample signal cliff occurs around 17 minutes into the test, with a relatively flat and stable reactance curve 550 B leading up to the signal cliff.
  • the signal cliff 565 represents a change AR in the reactance 560 B during a particular window of time Tw.
  • the signal cliff 565 indicates a positive sample.
  • the reactance curve 560 B is relatively flat or stable, and again after the signal cliff 565 the reactance curve 560 B is relatively flat or stable with slight concavity.
  • the signal cliff 565 for the particular test parameters represented by the plot 561 occurs as a peak, spike, or bell curve in the expected region 535 , during which the reactance values rise and fall by the AR value in an approximately parabolic curve.
  • varying of certain test parameters e.g., test well configuration, chemistry and initial quantity of amplification constituents, target, and excitation current characteristics
  • the geometry of a “signal cliff” in the reactance values vs time curve can vary from test to test, though for a particular test the curve geometry and/or timing signal cliff remains consistent within reactance change and/or timing parameters across positive samples for that test.
  • FIG. 6 depicts a schematic block diagram of an example reader device 600 that can be used with the cartridges described herein, for example the cartridges 120 or 200 .
  • the schematically illustrated reader device 600 may be, for example, the reader device 110 of FIGS. 1A-1C .
  • the reader device 600 includes a memory 605 , processor 610 , communications module 615 , heater 625 , electrode interface 630 , voltage source 635 , and a cavity 660 into which a cartridge can be inserted.
  • the reader device 600 may further include a status indicator 640 .
  • the reader device 600 is in communication with a user interface 620 , which may include a user interface of a remote computing device such as a smartphone, tablet, or other device having a testing control application executing thereon.
  • test cartridge 120 , 200 When test cartridge 120 , 200 is inserted into the cavity 660 of the reader device 600 , the electrode interface 214 of the cartridge couples with the electrode interface 630 of the reader device 600 . This can allow the reader device 600 to detect that a cartridge is inserted, for example by testing whether a communication path is established.
  • the optional power cartridges described above with reference to FIGS. 1B and 1C may activate a power supply circuit of the reader device 600 when the electrode interface 214 of the cartridge couples with the electrode interface 630 of the reader device 600 . Further, such communications can enable the reader device 600 to identify a particular inserted test cartridge 120 , 200 and access corresponding testing protocols.
  • Testing protocols can include the duration of the test, the temperature of the test, the characteristics of a positive sample impedance curve, and the information to output to the user based on various determined test results.
  • the reader device 600 can receive an indication via user interface 620 that a cartridge is inserted (e.g., by a user inputting a “begin testing” command and optionally a test cartridge identifier).
  • the memory 605 includes one or more physical electronic storage devices configured for storing computer-executable instructions for controlling operations of the reader device 600 and data generated during use of the reader device 600 .
  • the memory 605 can receive and store data from sensing electrodes coupled to the electrode interface 630 .
  • the processor 610 includes one or more hardware processors that execute the computer-executable instructions to control operations of the reader device 600 during a test, for example by controlling the heater 625 , controlling the communications module 615 to interact with the user interface 620 , and activating the voltage source 635 .
  • One example of testing operations is described with respect to FIG. 7A below.
  • the processor 610 can be also be configured by the instructions to determine test results based on data received from the excitation electrodes of an inserted test cartridge, for example by performing the process of FIG. 7B described below.
  • the communications module 615 includes network-enabled hardware components, for example wired or wireless networking components, for providing networked communications between the reader device 600 and remote computing devices. Suitable networking components include WiFi, Bluetooth, cellular modems, Ethernet ports, or USB ports, and the like. Beneficially, networking capabilities can enable the reader device 600 to interact with and be controlled by remote computing devices such as one or more additional handheld computing devices (e.g., smartphones, tablets, etc.). In some embodiments, remote devices may be in communication additional remote computing systems such as hospital information systems and/or laboratory information systems that store electronic medical records, national health agency databases, and the computing devices of clinicians or other designated personnel. In addition, the networking capabilities can enable the reader device 600 to receive information over the network from remote computing devices, for example updated signal cliff parameters for existing test, new signal cliff parameters for new tests, and updated or new testing protocols.
  • remote computing devices such as one or more additional handheld computing devices (e.g., smartphones, tablets, etc.).
  • remote devices may be in communication additional remote computing systems such as hospital information systems and/or
  • the user interface 620 can be implemented within a remote device connected to the communications module 615 via WiFi, or Bluetooth, or the like.
  • the remote device may have a testing control application installed thereon to provide a testing system user interface, for providing control options and/or presenting test results and other test information to users, on a display of the remote device. Further details of the user interface 620 are described with reference to FIGS. 8A-8D and FIGS. 15A-15P .
  • the heater 625 can be positioned adjacent to the cavity 660 for heating an inserted cartridge to the desired temperature for an amplification process. Though depicted on a single side of the cavity 660 , in some embodiments the heater 625 can surround the cavity.
  • the voltage source 635 can provide an excitation signal at a predetermined voltage and frequency to the excitation electrode of an inserted test cartridge.
  • the status indicator 640 may include any suitable notification device, such as one or more lights, sound generators, or the like. Operation of a light-based status indicator is described in greater detail with reference to FIGS. 1A-1C .
  • FIG. 7A depicts a flowchart of an example process 700 for operating a reader device during a test as described herein.
  • the process 700 can be performed by the reader device 600 described above.
  • the reader device 600 can detect that a power cartridge has been removed from the reader device 600 .
  • the detection of block 705 can occur based on the disconnection of a signal path between the electrode interface 630 of the reader device 600 and one or more contact pads 214 1 - 214 5 ( FIG. 2D ) of the power cartridge.
  • the reader device 600 automatically powers on in response to detecting the removal of the power cartridge at block 705 .
  • the reader device may transmit a notification to a user interface 620 device and/or illuminate one or more status lights of a status indicator 640 to indicate that the reader device 600 is powered on and ready to receive an assay cartridge 120 , 200 .
  • the reader device 600 can detect that an assay cartridge 120 , 200 , has been inserted, for example in response to user input or in response to establishing a signal path with the inserted cartridge.
  • the cartridge 120 , 200 can include an information element that identifies the particular test(s) to be performed to the reader device 600 and optionally includes test protocol information.
  • the reader device 600 can heat the cartridge 120 , 200 to a specified temperature for amplification.
  • the temperature can be provided by information stored on the cartridge 120 , 200 or accessed in the internal memory of the reader device 600 in response to identification of the cartridge 120 , 200 .
  • the reader device 600 can determine whether the test is still within its specified test duration. For example, where the expected window of time in which a signal cliff should appear in a positive sample is known, the duration of the test may end at or some predetermined period of time after the end of the window. If so, the process 700 transitions to optional decision block 730 or, in embodiments omitting block 730 , to block 735 .
  • the reader device 600 determines whether to monitor the test well amplification by logging data from the test well sensing electrode. For example, the reader 600 may be provided with instructions to only monitor the impedance of the test well during a particular window or windows of a test. If the reader device 600 determines not to monitor the test well amplification, the process 700 loops back to decision block 725 .
  • the process 700 transitions to block 735 .
  • the reader device 600 provides an excitation signal to the excitation electrode of the test well(s) of the inserted cartridge. As described above, this can be an alternating current at a particular frequency and voltage.
  • the reader device 600 detects and logs data from the sensing electrode of the test well(s) of the inserted cartridge. In some embodiments, this data can be stored for later analysis, for example after completion of the test. In some embodiments, the reader device 600 can analyze this data in real time (e.g., as the test is still occurring) and may stop the test once a positive sample signal cliff is identified.
  • the process 700 moves to block 745 to analyze the test data and output the test result.
  • the test result can include an indication that the sample tested positive or negative for the target, or can more specifically indicate an estimated quantity of the target in the tested sample.
  • further tests may be performed by returning to block 715 for a new assay cartridge.
  • the reader device 600 may detect insertion of a power cartridge and power off in response.
  • the reader device 600 can access logged signal data received from the electrode of a well.
  • the reader device 600 can generate a curve of the reactance values over time. Also at block 765 , the reader device 600 can optionally generate a curve of the resistance values over time.
  • FIG. 8A depicts an initial pre-test screen which may be displayed after an inserted assay cartridge 120 , 200 has been detected.
  • a user scans a cartridge identifier (e.g., cartridge identifier 215 of FIG. 2B ) of a cartridge before inserting the cartridge into the reader device.
  • the paired reader device detects the inserted cartridge and sends a message to the user interface device that the cartridge has been inserted.
  • the application displays the initial pre-test screen depicted in FIG. 8A .
  • the initial pre-test screen includes a status indication area 805 , a test identifying area 810 , a progress indication area 815 including a numeric progress indication 817 and a graphical progress indication 819 , and an input area 820 .
  • the status indication area 805 may include an instruction, such as a request for the user to confirm the information in the test identifying area 810 .
  • the test identifying area 810 includes information associated with the test to be performed, such as a name or other identifier of a test subject, a condition or target agent to be detected, or the like.
  • the input area 820 includes user-selectable “cancel” and “start test” options to allow the user to cancel the test or confirm the details and start the test.
  • FIG. 8B depicts a mid-test screen that may be displayed while the reader device is conducting the test on the fluid sample within the cartridge.
  • the status indication area 805 indicates that the test is in progress.
  • the numeric progress indication 817 and the graphical progress indication 819 are updated to display the current progress of the test.
  • a user-selectable option to cancel the test is provided in the input area to allow a user to stop the test if desired.
  • FIG. 8C depicts an initial test completion screen that may be displayed when the reader device has completed the test and has analyzed the logged test data to determine a test result.
  • the status indication area 805 , numerical progress indication 817 , and/or the graphical progress indication 819 may indicate that the test is complete.
  • the input area 820 a user-selectable option to view the test results is provided.
  • FIGS. 9A and 9B depict a further example of a handheld detection system 900 for detection of a target. Similar to the system 100 of FIGS. 1A-1C , the system 900 may be implemented in conjunction with any of the target detection processes, systems, and devices described herein.
  • the system 900 includes a reader device 910 and a cartridge 920 configured to fit within a cavity 912 of the reader device 910 .
  • the cartridge 920 is sized and shaped to be gripped by a user to facilitate insertion and/or removal of the cartridge 920 from the reader device 910 .
  • the reader device 910 may further include a light ring 914 disposed about the cavity 912 .
  • the light ring 914 may include any or all of the light sources, colors, operation modes, etc., described above with reference to the light ring 114 of FIGS. 1A-1C .
  • FIGS. 10A and 10B depict a complete cartridge 1000 including the cartridge body 1010 and the cap 1050 coupled together.
  • the cap 1050 and the cartridge body 1010 can operate to seal a provided sample within the cartridge 1000 , thereby preventing exposure of test operators to the sample and preventing any liquid from escaping into the electronics of an associated reader device.
  • the cartridge body 1010 and the cap 1050 may be coupled by a friction fit, a snap fit, and/or one or more mechanical or chemical securing means. Coupling of the cartridge body 1010 and the cap 1050 is discussed in greater detail with reference to FIGS. 11A-11D .
  • the cartridge identifier 1011 can include any suitable information associated with the cartridge, such as information specifying a type of test, a target agent, a sample type, a cartridge serial number or other individual cartridge identifier, etc.
  • the cartridge identifier 1011 may also be scanned by a user (e.g., using a user interface device in communication with a reader device) to communicate one or more test protocols to the reader device.
  • the cartridge body 1010 and/or the cap 1050 can include ergonomic features such as an indentation or the like to facilitate handling of the cartridge 1000 .
  • the cartridge body 1010 further includes an alignment groove 1012 located to align with an alignment groove 1052 of the cap 1050 .
  • the alignment groove 1052 of the cap 1050 terminates at a stop 1054 configured to engage a protrusion within a corresponding reader device (e.g., the reader device 910 of FIGS. 9A and 9B ) to define a fully inserted position of the cartridge 1000 within the reader device.
  • the cap 1050 can further include a sample receiving area cap 1056 sized and shaped to sealingly close an opening in the cap 1050 for receiving a swab or other sample carrying holding a sample to be analyzed.
  • FIGS. 10C and 10D depict the cap 1050 component of the cartridge 1000 of FIGS. 10A and 10B .
  • the cap 1050 comprises an elongate body which is at least partially hollow to receive a sample carrier such as a swab or the like.
  • An opening in the cap 1050 for receiving the sample carrier may be sealed by the sample receiving area cap 1056 , which may include one or more O-rings or other resilient structures to sealingly block the opening in the cap 1050 .
  • the cap 1050 further includes a collar 1058 protruding from the cap 1050 .
  • the collar 1058 is sized and shaped to facilitate coupling with the cartridge body 1010 .
  • the collar 1058 generally comprises a hollow cylindrical body defining a plunger receiving well 1060 through which the fluid sample may pass from the cap 1050 into the cartridge body 1010 .
  • the collar 1058 includes interlocking fins 1062 extending radially outward from an exterior surface of the collar 1058 , and receiving channels 1064 within the an interior surface of the collar 1058 .
  • Each receiving channel 1064 terminates in a widened section 1065 such that the receiving channels 1064 are configured to receive and retain one or more snap-fit connectors of the cartridge body 1010 , as will be described with reference to FIGS. 11A-11D .
  • the cap 1050 may further include one or more liquid constitutent therein to be mixed with a received sample.
  • liquid constituents may include one or more amplification reagents, buffer solutions, water, mucin mitigating agents, or other desired liquid constituents for the testing process. The particular selection and chemistry of these liquids can be tailored to a particular target or targets for which the cartridge 1000 is designed to test.
  • the liquid constituents may be contained within a blister pack within the cap 1050 .
  • the blister pack may be punctured by, for example, insertion of a sample carrier, coupling of the cap 1050 to the cartridge body 1010 , etc.
  • FIGS. 10E-10K depict the cartridge body 1010 component of the cartridge 1000 of FIGS. 10A and 10B .
  • FIGS. 10E-10G are exterior views of the cartridge body 1010 .
  • FIGS. 10H-10J depict the cartridge body 1010 with partial translucency to illustrate fluid paths integrally formed therein.
  • FIG. 10K is an enlarged view depicting the PCB 1014 of the cartridge body 1010 .
  • the cartridge body 1010 includes a base 1016 and a hollow plunger 1018 rotatably coupled within a receiving well 1026 of the base such that the plunger 1018 can rotate about its longitudinal axis while being retained within the receiving well 1026 .
  • the plunger 1018 comprises a generally cylindrical body sized and shaped to fit within the plunger receiving well 1060 of the cap 1050 ( FIGS. 10C and 10D ).
  • a sealing portion 1020 of the plunger 1018 is disposed at a distal end of the plunger 1018 and may include one or more resilient structures (e.g., one or more O-rings, integrally formed elastomeric structures, etc.) having an appropriate diameter to sealingly engage with the interior walls of the plunger receiving well 1060 of the cap 1050 .
  • a sacrificial seal 1024 such as a layer of a metallic foil or other thin material may be provided to prevent exposure of the interior of the cartridge body 1010 to the atmosphere prior to use.
  • one or more liquid constituents may be included within the plunger 1018 , instead of or in addition to liquid constituents included within the cap 1050 .
  • the sacrificial seal 1024 may contain the liquid constituents within the plunger 1018 and/or the liquid constituents may be contained within a blister pack within the plunger 1018 .
  • Liquid constituents contained within the plunger may include one or more amplification reagents, buffer solutions, water, mucin mitigating agents, or other desired liquid constituents for the testing process. The particular selection and chemistry of these liquids can be tailored to a particular target or targets for which the cartridge 1000 is designed to test.
  • the blister pack may be punctured by, for example, insertion of a sample carrier, coupling of the cap 1050 to the cartridge body 1010 , etc.
  • the receiving well 1026 is coaxial with the plunger 1018 and has a generally cylindrical profile with a diameter substantially equal to or slightly larger than the plunger baseplate 1019 and/or the collar 1058 of the cap 1050 .
  • the receiving well 1026 further includes cutouts 1028 sized to receive the interlocking fins 1062 of the cap 1050 . Stops 1030 within the cutouts 1028 are disposed within the cutouts 1028 to block longitudinal motion of the interlocking fins 1062 in certain rotational positions, as will be described in greater detail with reference to FIGS. 11A-11D .
  • FIGS. 10H-10J depict additional views of the cartridge body 1010 in which the base 1016 is illustrated with transparency to show the fluid paths contained therein.
  • the base 1016 may comprise any suitable liquid-impermeable material, such as plastic or metal.
  • the base 1016 may be formed by one or more processes such as injection molding, die casting, milling, or the like, such that the depicted fluid paths can be integrally formed therein.
  • Each fluid path includes an inlet channel 1042 , a lateral channel 1044 , a test well 1040 , and an outlet channel 1046 .
  • Each inlet channel 1042 extends vertically through the base 1016 to fluidically connect a first end adjacent to the plunger baseplate 1019 to an opposite end adjacent to the PCB 1014 .
  • Each lateral channel 1044 fluidically connects an inlet channel 1042 to the corresponding test well 1040 .
  • Each outlet channel 1046 extends vertically from a test well 1040 to fluidically connect the test well 1040 to the bottom of the plunger baseplate 1019 .
  • the PCB 1014 forms a boundary partially defining each lateral channel 1044 and each test well 1040 .
  • the PCB 1014 may be oriented with the electrodes 1036 , 1038 on the side adjacent to the cartridge body 1010 such that the electrodes 1036 , 1038 are in contact with the interior of the test wells 1040 .
  • each inlet channel 1042 is disposed radially outward from the longitudinal axis of the plunger baseplate 1019 at substantially the same distance as an array of sample inlets 1041 of the plunger baseplate 1019 .
  • each outlet channel 1046 is disposed radially outward from the longitudinal axis of the plunger baseplate 1019 at substantially the same distance as the outer ends of an array of J-shaped sample outlets 1048 of the plunger baseplate 1019 .
  • the sample inlets 1041 and the inner ends of the J-shaped sample outlets 1048 are fluidically connected through the plunger baseplate 1019 to one or more interior spaces within the plunger 1018 .
  • the sample inlets 1041 align with the inlet channels 1042
  • the sample outlets 1048 align with the outlet channels 1046 , such that a fluid sample within the plunger 1018 can flow into and fill the fluid paths within the base 1016 of the cartridge body 1010 .
  • FIG. 10K illustrates components of the PCB 1014 , which may be disposed along a surface of the cartridge body 1010 opposite the receiving well 1026 as shown in FIGS. 10E-10K .
  • the PCB 1014 may perform heating and/or electrode interface functions, and may further serve as a boundary for one or more fluid paths within the cartridge body 1010 .
  • the example PCB 1014 depicted herein includes heating and electrode interface functionality, these functions may equally be performed by two or more discrete elements in the cartridge body 1010 .
  • heating may be achieved by heating elements located within a corresponding reader device instead of or in addition to heating elements disposed on or in the cartridge 1000 .
  • the PCB 1014 comprises a generally planar surface having one or more traces disposed thereon in one or more layers.
  • the PCB 1014 may include one or more flex circuits, rigid printed circuit boards, or any other suitable circuitry including one or more current paths disposed on a generally planar substrate.
  • One or more heating traces 1032 electrically connect test well heating elements 1033 to heating current pads 1034 .
  • the heating current pads 1034 may come into contact with contacts of a current source of a reader device when the cartridge 1000 is inserted into the reader device, such that a current may be provided to the test well heating elements 1033 to heat fluid samples in one or more test wells of the cartridge body 1010 .
  • the PCB 1014 further comprises a pair of electrodes 1036 , 1038 (e.g., an excitation electrode and a sensor electrode) corresponding to each test well.
  • the electrodes 1036 , 1038 may be in direct contact with the fluid sample in each test well if the PCB 1014 serves as a boundary for the test wells.
  • Each electrode 1036 , 1038 is electrically connected to an electrode interface pad 1035 by electrode traces 1037 , 1039 of the PCB 1014 .
  • the PCB 1014 may include one or more layers.
  • the PCB is a flex circuit comprising an electrode layer and a heating layer separated from the electrode layer.
  • the electrode layer may include the electrodes 1036 , 1038 as well as the electrode traces 1037 , 1039 and/or the electrode interface pads 1035 .
  • the heating layer may include the heating elements 1033 , heating traces 1032 , and/or heating current pads 1034 .
  • the electrode layer and the heating layer may be disposed on opposite sides of a common substrate, or may be provided on separate substrates.
  • the PCB 1014 may be disposed such that the electrode layer including the electrodes 1036 , 1038 is adjacent to the cartridge body 1010 and the electrodes 1036 , 1038 are fluidically connected to the test wells 1040 .
  • FIGS. 11A-111D illustrate mechanical fluid transfer aspects of the cartridges 920 , 1000 described herein. Similar to the fluid transfer aspects described with reference to FIGS. 3A-3E , the cartridge body 1010 and cap 1050 are configured to create air pressure when coupled together, such that the air pressure propels a fluid sample through the fluid paths of the cartridge body 1010 .
  • the cap 1050 is illustrated with translucency in FIGS. 11A-11D
  • the cartridge body 1010 is illustrated with translucency in FIGS. 11C and 11D , to reveal interior features of the cap 1050 and cartridge body 1010 .
  • the cartridge body 1010 is depicted with the PCB 1014 removed in FIG. 11C .
  • a fluid sample may be received within the cap 1050 .
  • a swab or other sample carrier may be inserted into an opening of the cap 1050 opposite the cartridge body 1010 , and the opening may then be sealed by the sample receiving area cap 1056 to contain the sample within the cap (e.g., within the plunger receiving well 1060 or other internal space within the cap 1050 .
  • the process of FIGS. 11A-11D may be used to mechanically couple the cartridge body 1010 to the cap 1050 and move the fluid sample into the cartridge body 1010 .
  • the mechanical coupling of the cartridge body 1010 and the cap 1050 begins by inserting the plunger 1018 of the cartridge body 1010 into the plunger receiving well 1060 of the cap 1050 .
  • the sealing portion 1020 of the plunger 1018 can sealingly engage with the interior of the plunger receiving well 1060 to trap and begin compressing a volume of air within the plunger receiving well 1060 .
  • the snap-fit clips 1022 slide within the receiving channels 1064 until they pass into the widened sections 1065 of the receiving channels 1064 , where they are longitudinally retained.
  • Retention of the snap-fit clips 1022 within the receiving channels 1064 prevents removal of the cap 1050 from the cartridge body 1010 , and further locks the cap 1050 rotationally with the plunger 1018 , thereby allowing a user to rotate the plunger 1018 and plunger baseplate 1019 by rotating the cap 1050 , which may be relatively large and easy to manipulate manually.
  • the cap 1050 and cartridge body 1010 may slide together until the collar 1058 of the cap 1050 is partially within the receiving well 1026 of the cartridge body 1010 and the interlocking fins 1062 of the collar 1058 contact the stops 1030 ( FIG. 10F ) within the cutouts 1028 .
  • the cap 1050 , plunger 1018 , and plunger baseplate 1019 may then be rotated about the longitudinal axis. Because the snap-fit clips 1022 rotationally fix the plunger 1018 to the cap 1050 , rotation of the plunger 1018 and plunger baseplate 1019 may be achieved by rotating the cap 1050 .
  • the cap 1050 may rotate until the interlocking fins 1062 are blocked by a lateral side of the cutouts 1028 of the receiving well 1026 .
  • the cutouts 1028 and interlocking fins 1062 are sized to allow a total rotation of approximately 22.5° while the interlocking fins 1062 are within the cutouts 1028 .
  • example cartridges may function with a different range of rotational motion, such as between approximately 5° and approximately 90°, between approximately 100 and approximately 45°, between approximately 150 and approximately 30°, between approximately 200 and approximately 25°, or any angle or subrange of angles therebetween.
  • the rotation of components in FIG. 11B may cause the blister pack to be punctured so as to release the liquid constituents to mix with the sample.
  • the cap 1050 may be moved downward along the longitudinal axis, such that the collar 1058 moves further into the receiving well 1026 . Because the stops 1030 only extend along a portion of the cutouts 1028 , the rotational motion described with reference to FIG. 11B moves the interlocking fins 1062 clear of the stops 1030 such that the interlocking fins 1062 can move to an interior portion 1029 of the cutouts 1028 . As shown in FIG. 11C , the rotated position of the plunger baseplate 1019 substantially aligns the inlet channels 1042 and the outlet channels 1046 with the sample inlets 1041 and the sample outlets 1048 , respectively. When the cap 1050 is pressed further onto the cartridge body 1010 to the position of FIG.
  • the sample carrier and/or one or more internal structures within the cap 1050 may mechanically contact and rupture a seal on or within the plunger 1018 (e.g., the sacrificial seal 1024 of FIG. 10F ), thereby allowing the trapped air compressed by the plunger 1018 to flow into the interior of the plunger and propel the fluid sample through the plunger baseplate 1019 and into the fluid paths of the cartridge body 1010 .
  • the longitudinal motion of components in FIG. 11C may cause the blister pack to be punctured so as to release the liquid constituents to mix with the sample.
  • FIG. 11C illustrates the flow of a portion of a fluid sample through a single example fluid path 1105 within the cartridge body 1010 with encircled numbers shown as labels for certain points along the fluid path.
  • the encircled numbers are discussed below as example steps of a progression of a fluid sample as it travels through the flow path 1105 .
  • each step including a directional arrow showing the direction of fluid travel at that step.
  • step (1) as the compressed air is allowed to flow into the plunger 1018 , the fluid sample is forced through the sample inlet 1041 into the inlet channel 1042 .
  • the fluid sample travels along the inlet channel 1042 toward the lateral channel 1044 .
  • the fluid sample reaches the PCB 1014 boundary of the fluid path, and begins traveling parallel to the PCB 1014 within the lateral channel 1044 .
  • the fluid sample continues through the curved lateral channel 1044 toward the test well 1040 .
  • the fluid sample enters the test well 1040 .
  • the test well 1040 may contain one or more reagents. Agitation caused by the turbulent flow of the fluid sample within the relatively larger space of the test well 1040 causes the reagent and the sample to be mixed.
  • the reagent and the fluid sample are mixed into a homogeneous solution in which the reagent is evenly distributed throughout the fluid sample.
  • the depth, width, shape, and/or cross-sectional profile of the test well 1040 may be selected to facilitate mixing of the reagent and the fluid sample.
  • any excess fluid sample is pushed from the test well 1040 into the outlet channel 1046 and enters the outer end of the J-shaped sample outlet 1048 .
  • the excess fluid sample reaches the inner end the sample outlet 1048 , it passes through a corresponding opening in the plunger baseplate 1019 at step (6) and is vented into the plunger 1018 .
  • the interior volume of the plunger 1018 and/or the cap 1050 is separated from the interior volume that is fluidically connected to the sample inlet 1041 , so as to create a directional flow of fluid sample along the fluid path 1105 .
  • the cartridge 1000 may reach a pressure equilibrium as the compressed air forces the fluid sample into the fluid path 1105 , the fluid path 1105 is filled with the fluid sample, and a portion of the sample is vented back into the plunger 1018 and/or the cap 1050 .
  • the pressure equilibrium may be reached relatively quickly, for example, within 10 seconds, 5 seconds, 2 seconds, 1 second, or less.
  • the cap 1050 , plunger 1018 , and plunger baseplate 1019 may again be rotated relative to the cartridge body 1010 .
  • the above components are rotated by the same angular displacement, but in the opposite direction, relative to the rotation of FIG. 11B .
  • the plunger baseplate 1019 rotates relative to the fluid path 1105 such that the inlet channels 1042 and outlet channels 1046 are no longer aligned with the sample inlets 1041 and sample outlets 1048 , thereby sealing the fluid path 1105 and retaining the fluid sample within the test wells 1040 for testing.
  • This final rotation step additionally causes the interlocking fins 1062 of the cap 1050 to be retained under the stops 1030 within the interior portion 1029 of the receiving well cutouts 1028 , completing and securing the mechanical coupling of the cartridge body 1010 and cap 1050 .
  • the final rotation step substantially aligns the exterior profiles of the cartridge body 1010 and the cap 1050 such that the assembled cartridge 1000 can be inserted into a reader device to perform one or more tests on the fluid sample contained therein.
  • FIGS. 12A-12I illustrate a further embodiment of a cartridge 1200 configured for detection of a target.
  • the target may be a viral target, bacterial target, antigen target, parasite target, microRNA target, or agricultural analyte.
  • Some embodiments of the cartridge 1200 can be configured for testing a single target, while some embodiments of the cartridge can be configured for testing for multiple targets.
  • the cartridge 1200 includes a cartridge body 1202 and a swab assembly 1220 configured to be mechanically coupled to the cartridge body 1202 at a swab assembly insertion point 1208 .
  • the cartridge body 1202 includes a thin film testing assembly 1204 and an ergonomic frame 1206 configured to be grasped by a user.
  • the thin film testing assembly 1204 generally includes a plurality of test wells 1258 , pinch valves 1214 for isolating fluid within the test wells 1258 , a gas permeable filter 1212 such as a membrane or the like, and an electrode interface 1210 for electrically connecting electrodes at the test wells to circuitry of a reader device.
  • the cartridge further includes a fluidic piston 1218 and a transition point 1216 for introducing a fluid sample from the swab assembly 1220 into the thin film testing assembly 1204 .
  • the features of the thin film testing assembly 1204 are discussed in greater detail with reference to FIGS. 12H and 12I .
  • the swab assembly 1220 includes a tube 1222 , a slider 1224 , and a cap 1234 configured to fit together to form a substantially sealed swab assembly 1220 .
  • the tube 1222 includes a tube channel 1226 sized and shaped to receive a shaft 1236 of the cap 1234 .
  • the tube channel 1226 may be sealed, such as with a foil seal or the like, to contain one or more liquid reagents, buffers, etc., during shipping and/or prior to use of the swab assembly 1220 .
  • the tube channel 1226 may have an hourglass profile, a dual lobe profile, or other shape configured to facilitate mixing of fluids therein.
  • the tube channel 1226 may further include interior threading or other protruding features further configured to facilitate mixing of fluids with in the tube channel 1226 .
  • the slider 1224 comprises a hollow structure configured to fit around an engagement end 1223 of the tube 1222 .
  • the tube 1222 further includes one or more snap-fit clips 1232 configured to interlock with first and second snap-fit openings 1228 and 1230 of the slider 1224 .
  • the cartridge body 1202 includes an overhand that keeps the tube 1222 centered in a width of the cartridge body 1202 .
  • FIGS. 12E and 12F illustrate the cap 1234 .
  • FIG. 12E is a perspective view of the cap.
  • FIG. 12F is a cross-sectional view of the cap illustrating internal components thereof.
  • the cap 1234 comprises a hollow shaft 1236 surrounding a cap channel 1238 , and a hollow upper section 1244 surrounding a metered volume 1240 .
  • the upper section 1244 may further include a sealing portion 1242 comprising a resilient material (e.g., rubber, a resilient plastic, or other elastomeric material) sized and shaped to sealingly engage the interior of the slider 1224 .
  • a foil seal 1246 may seal one or more liquid and/or dried reagents within the cap 1234 .
  • a vent 1248 may be fluidically connected to the metered volume 1240 to allow any gas trapped within the cap 1234 to be vented.
  • the shaft 1236 terminates at a cap inlet 1250 fluidically connected to the cap channel 1238 , which may include one or more sections of a filter 1252 configured to allow fluid flow into the cap channel 1238 .
  • an additional seal may be provided over the cap inlet 1250 to seal any liquid and/or dried reagents within the cap 1234 prior to use.
  • a sample (e.g., a nasal swab or other swab-collected sample) may be received on a swab.
  • the slider 1224 Prior to inserting the swab into the swab assembly 1220 , the slider 1224 is moved along a first direction 1254 relative to the tube 1222 such that the snap-fit clips 1232 of the tube 1222 engage with the second snap-fit openings 1230 . This motion may cause an internal structure 1231 of the slider 1224 to break the foil seal at the opening of the tube to expose the liquid reagents or buffers contained within the tube channel 1226 .
  • the swab When the tube channel 1226 is exposed, the swab may be introduced into the tube channel 1226 such that the sample on the swab mixes with the liquid reagents within the tube channel 1226 .
  • the interior profile and/or other mixing features of the tube channel 1226 may facilitate mixing of the sample with the liquid reagents to form a test fluid.
  • the swab may be broken off from a handle such that the portion of the swab containing the sample remains within the tube channel 1226 .
  • the cap 1234 may be mechanically coupled to the tube 1222 and slider 1224 to complete the swab assembly 1220 . If a seal is provided around the cap inlet 1250 , the seal may be removed. The shaft 1236 of the cap is inserted through the slider 1224 , and the cap 1234 is pushed into the slider 1224 and the tube channel 1222 such that the sealing portion 1242 sealingly engages with the interior of the slider 1242 . As the cap 1234 continues to move along the direction 1254 , air and fluid are compressed within the tube channel 1222 to drive the mixed test fluid through the cap inlet 1250 and the cap channel 1238 into the metered volume 1240 .
  • any gas, such as air, present within the metered volume 1240 may be vented externally through the vent 1248 .
  • the filter 1252 at the cap inlet 1250 prevents solids, such as solids within the swab sample or pieces of the swab itself, from entering the cap 1234 .
  • the location of the cap inlet 1250 at an end of the tube channel 1226 distal from the metered volume 1240 may advantageously cause the inlet 1250 to receive an optimal portion of the test fluid in the event that the test fluid has not quite achieved a homogeneous mixture.
  • the swab assembly 1220 When the cap 1234 has been sealingly inserted into the tube 1222 and slider 1224 , the swab assembly 1220 is fully assembled, and any liquid therein is retained within the swab assembly 1220 by the foil seal 1246 of the cap 1234 . The swab assembly 1220 may then be placed into the swab assembly insertion point 1208 of the cartridge 1200 to introduce the test fluid to the thin film testing assembly 1204 .
  • the thin film testing assembly 1204 includes a substrate 1207 surrounding a plurality of test wells 1258 .
  • One boundary of the test wells 1258 is formed by a cover film 1205 including a plurality of pinch valves 1214 which form a portion of a fluid flow path into the thin film testing assembly 1204 .
  • a pair of electrodes 1260 which may be formed consistent with any of the electrodes described elsewhere herein, are provided within each test well 1258 and electrically connected to electrode connection pads 1211 of the electrode interface 1210 for connection to a reader device.
  • the fluid within the metered volume 1240 of the swab assembly 1220 flows through the transition point 1216 and along a fluid path within the thin film testing assembly 1204 to fill the test wells 1258 .
  • Any gas such as air within the thin film testing assembly 1204 may be displaced from the test wells 1258 and vented at a vent 1262 and/or at the gas permeable filter 1212 .
  • the cartridge 1200 may then be inserted into a reader device sized and shaped to receive the cartridge 1200 .
  • the reader device As the cartridge 1200 is inserted into the reader device (in a direction of the arrow in FIG. 12A ), electrical contacts within the reader device come into contact with the electrode connection pads 1211 of the cartridge 1200 .
  • the opening within the reader device for receiving the cartridge 1200 has a width selected such that an interior surface of the reader device compresses and/or crushes the pinch valves 1214 , preventing fluid flow therethrough after the cartridge 1200 has been inserted into the reader device.
  • the pinch valves 1214 may comprise a thermoformed plastic or other material selected such that the pinch valves 1214 can be compressed and closed off without breaking and allowing the test fluid to escape.
  • test fluid within each test well 1258 is fluidically isolated within the test well 1258 for testing. Heating and testing of the test fluids in the test wells 1258 may then proceed as described above with reference to the cartridges 200 , 1000 .
  • the test wells 1258 may be pre-loaded with one or more primers (e.g., spot-dried, powdered, or other non-liquid primers) or other reagents corresponding to the tests to be performed and/or target agents to be detected in each test well 1258 .
  • Some or all of the test wells 1258 may include the same or different primers as the primers present in the other test wells 1258 , depending on the individual test to be performed and/or target agents to be detected in each test well 1258 .
  • FIGS. 13A-13E depict an example of another type or format of cartridge 1300 configured to detect a target, such as a nucleic acid e.g., a desired DNA or RNA sequence, which can be used in conjunction with one or more of the handheld systems disclosed herein.
  • a target such as a nucleic acid e.g., a desired DNA or RNA sequence
  • the target may be a viral target, bacterial target, antigen target, parasite target, microRNA target, or agricultural analyte.
  • such targets are selected viral, bacterial, parasite, microRNA, or agricultural DNA or RNA sequences e.g., sequences complementary to selected primers designed to identify the presence or absence of such targets.
  • the cartridge 1300 can be configured for testing for the presence or absence of a single target, while some embodiments of the cartridge 1300 can be configured for testing for multiple targets, optionally simultaneously or within a short time after the first identified result.
  • the cartridge 1300 may be configured to test for enzymes (for example, in the evaluating and/or analyzing for enzyme replacement therapy).
  • the cartridge 1300 may be configured to test for environmental contaminants such as pesticide residues (e.g., glyphosphate, and so forth), heavy metals, benzene residues, and so forth.
  • the cartridge 1300 may be configured to test for or identify pathogens, genomic materials, proteins, and/or other small molecules or biomarkers.
  • the cartridge 1300 may be configured to test for and/or identify elevated prostate-specific antigen (PSA) levels, elevated cells counts, low cell counts, tumor cells, and so forth, for use in oncology applications.
  • the cartridge 1300 may be configured to identify and/or test for microRNA or used to test for infections, diseases, and so forth often of concern with respect to food safety and/or plasma and/or blood screenings.
  • the cartridge 1300 may be further configured to identify and/or test for rare infectious diseases, tick and/or mosquito borne (or other insect, plant, and/or animal vector borne) diseases.
  • the cartridge 1300 may be configured to test for and/or identify norovirus and/or rotavirus, for example in water quality applications.
  • the cartridge 1300 is configured to test for anything any of the other cartridges described herein test for, and vice versa.
  • the cartridge 1300 includes, among other components, a cartridge body 1302 , a cover 1314 , electrodes 1304 , and a cap 1310 . These components will be described in further detail below.
  • the cartridge body 1302 may be thermoformed from a polyethylene or similar plastic material.
  • the cartridge body 1302 may house various components and/or features of the cartridge 1300 .
  • the cartridge body 1302 may house at least a portion of the electrodes 1304 , a swab receptacle 1342 , a sample mixing and microfiltration region 1330 (described further below), a reagent stored in a reagent blister 1340 , and an integrated reagent blister rupture feature 1344 , a distribution tree 1328 for a sample/reagent mixture from the sample mixing and microfiltration region 1330 , an exhaust port 1326 to vent gases, a degassing gas-permeable membrane 1320 , and a plurality of reaction wells 1322 configured to allow the electrodes 1304 to generate signals based on the sample/reagent mixture.
  • the cartridge body 1302 also includes a thumb detent configured to be grasped by a user to facilitate removal of the cartridge 1300 from the analyzer, described in further detail below.
  • the cartridge body 1302 also, optionally includes an isolation cap 1310 or a locking isolation cap 1310 configured to isolate, close, or protect the swab receptacle 1342 from external variables.
  • the cover 1314 of the cartridge body 1302 may be thermoformed from a plastic or similar material and includes an exhaust port crush valve 1306 and well isolations crush valves 1312 .
  • the well isolations crush valves 1312 may isolate fluid within the plurality of reaction wells 1322 .
  • the reaction wells 1322 may function similarly to the test wells 1258 described above.
  • the electrodes 1304 may electrically connect electrodes at the reaction wells 1322 to circuitry of a reader device described further below.
  • the electrodes 1304 may function similarly to the electrode interface 1210 described above.
  • the swab receptacle 1342 includes a tapering, tubular portion 1348 , a scraper portion 1350 , dispensing portion 1352 , and the isolation cap 1310 or the locking isolation cap 1310 .
  • the isolation cap 1310 or the locking isolation cap 1310 and the swab receptacle 1342 are configured to fit together to form a sealed or substantially sealed swab assembly.
  • the tapering, tubular portion 1348 includes a tapering tube channel sized and shaped to receive a swab including mucus or another sample and to be sealed or substantially sealed by the isolation cap 1310 or locking isolation cap 1310 .
  • the reagent blister 1340 may contain one or more reagents (for example, a liquid reagent, a buffer, etc.) during shipping and handling before the cartridge 1300 is inserted into the corresponding analyzer.
  • the reagent blister 1340 includes only reagents in a liquid form.
  • the reagent blister may comprise a sealed compartment, for example sealed with a foil seal or the like, similar to the sealed channel 1226 described above.
  • the sample mixing and macrofiltration region 1330 may be configured and operate to facilitate mixing of fluids and so forth therein (for example, the sample with the reagent).
  • the tapering, tubular portion 1348 may further include the scraper 1350 configured to facilitate acquisition of the sample from the swab inserted into the swab receptacle 1342 . Further details are provided below.
  • the cartridge body 1302 includes snap-fit clips 1346 that may lock and/or engage with snap-fit openings to interlock and hold the cartridge body 1302 together, similar to the snap-fit clips 1232 and snap-fit openings 1228 described above.
  • the cartridge 1300 may be used in conjunction with an analyzer, similar to the analyzer or reader device (for example, reader device 110 , 600 , or 910 ) described above with reference to the cartridges described above (for example, cartridge 120 , 200 , 1000 , and 1200 ).
  • the analyzer also referred to herein as the “reader device”
  • the application may provide the operator or patient with a view of the results from the analysis of the cartridge as well as an option for the patient to input particular symptoms being suffered.
  • the application may communicate with a cloud storage system (or similar storage) to store data from the application that is received from or via the analyzer.
  • the analyzer, application, and cloud storage may enable secure communications and may aggregate information from various cartridge samples to enable treatment decisions (for example, identify that a sample being tested with a cartridge indicates a particular sickness, etc., based on a comparison of the analysis results from the analyzer with results from a historical database of analyses and corresponding sickness, etc., determinations.
  • FIGS. 14A and 14B depict an example of the other handheld analyzer system 1400 disclosed herein.
  • the analyzer 1400 includes the features described above of other analyzers, including a slot for insertion of the cartridge, for example the cartridge 1300 .
  • the analyzer 1400 comprises a printed circuit board (PCB) 1402 on which various electrical components are disposed and electrically connected.
  • the PCB 1402 includes a communication or charging port, such as a USB (or similar) port 1404 .
  • the PCB 1402 further includes a microprocessor 1406 and a digital signal processor (DSP) 1408 .
  • the PCB 1402 further comprises an analog sub-section 1410 and cartridge mating connectors 1412 to electronically couple to the cartridge 1300 .
  • the PCB 1402 further comprises a cryptographic processor 1414 , a battery controller 1416 , and storage 1418 .
  • the PCB 1402 may also include one or more mounting holes or devices 1420 .
  • the application Before operating the cartridge and the analyzer 1400 , the application may be used to select a particular cartridge 1300 that will be used with the analyzer 1400 . In some embodiments, the selection may comprise indicating one or more parameters associated with the particular cartridge 1300 to the analyzer 1400 .
  • a swab may be used to collect a fluid sample (for example, a nasal fluid or sputum sample). The swab with the fluid sample from the patient may be pressed into the swab receptacle 1342 until the swab stops moving into the swab receptacle 1342 .
  • a surface tension of the fluid sample that is wetted to the walls is sufficient to retain at least a portion of the fluid sample in the swab receptacle 1342 (for example, a reservoir portion of the swab receptacle 1342 ).
  • the fluid sample to be analyzed by the analyzer is removed from the fluid sample initially collected on the swab and remains in place as the cap 1310 is closed, sealing or substantially sealing the swab receptacle 1342 and the cartridge 1300 .
  • the flow of the mixed sample and reagent may terminate at the exhaust gas-permeable membrane 1324 located at the exit of each reaction well 1322 , thereby ensuring uniform filling in each well. All of these processes may occur before the cartridge 1300 is inserted into the analyzer 1400 .
  • these other fluidic channel components act as isolation valves for each individual reaction well 1322 .
  • the well isolation crush valves 1312 act as isolation valves for each individual reaction well 1322 .
  • passive features located on the upper mating surface of the analyzer 1400 “crush” the isolation crush valves 1312 (which may comprise thin channels) down against the PSA bonding the thermoformed cover 1312 or a film to the injection molded cartridge body 1302 .
  • the PSA conforms to the deformed shape of the thin film channel in the cartridge body 1302 , serving to isolate the reaction well 1322 fluidically from the channels that join the reaction wells 1322 together fluidically. This isolation may prevent crosstalk and diffusion from reaction well 1322 to reaction well 1322 . Additionally, this isolation may serve to isolate the reagents and the byproducts of the reaction from the analyzer 1400 and user.
  • the well-isolation crush valves 1312 may protrude from an upper surface of the thermoformed cover 1314 on the cartridge body 1302 so that they are crushed when the cartridge 1302 is inserted into the analyzer 1400 .
  • an upper heater is mounted to an integrated crossbar and leaf spring of the analyzer 1400 .
  • two cam runners are positioned in a cartridge receptacle of the analyzer 1400 such that when the cartridge 1300 begins to be inserted, the cam runners push the upper heater up and out of the way of the crush valves (for example, the well isolation crush valves 1312 and/or the exhaust port crush valve 1306 ) disposed on the thermoformed cover 1312 .
  • the cam runners continue to pass along an upper edge of the cartridge body 1302 until the cam runners arrive at a molded drop in the upper edge of the cartridge body 1302 .
  • the cartridge 1300 is fully inserted into the analyzer 1400 , the mixed sample and reagent are distributed to the reaction wells 1322 and isolated in each reaction well 1322 .
  • the upper heater in the analyzer 1400 may uniformly contact the upper surface of the cartridge body 1302 , sandwiching the cartridge body 1302 against a lower heater in the analyzer 1400 .
  • the cartridge 1300 may also establish an electrical connection to the analyzer 1400 via the flexible electrode layer 1304 , thereby enabling the analyzer 1400 to begin a test of the mixed sample and reagent in the reaction wells 1322 .
  • the method for using the cartridge 1300 with the analyzer 1400 to detect a target involves first collecting a sample fluid from a patient or user.
  • the sample fluid may be collected using a swab or other similar sample collecting method or means. Once the sample fluid is collected, the sample fluid is introduced into the cartridge 1300 .
  • the swab is inserted into the cartridge 1300 via the swab receptacle 1342 .
  • the optional cartridge cap 1310 may be closed and the cartridge 1300 may be inserted into the analyzer 1400 .
  • the insertion of the cartridge 1300 may cause a reagent blister 1340 to rupture and mix the reagents contained therein with the sample fluid.
  • the mixture of the reagents and the sample fluid is conveyed to the reaction wells 1322 .
  • the reaction wells 1322 may each have a volume of approximately 25 microliters ( ⁇ L).
  • the reaction wells 1322 has a volume, size, and/or shape that is based on the overall volume of liquid which will fill the reaction wells 1322 as well as a favorable geometry above the sensing electrode.
  • the reaction wells 1322 are circular, triangular, or rectangular, or any other polygonal shape.
  • the electrodes 1304 (or corresponding circuitry and/or circuit board components/parameters) of the cartridge 1300 may enable the analyzer 1400 to simultaneously test each of the reaction wells 1322 (for example, each representing a different channel) at a plurality of frequencies (for example, three (3) frequencies).
  • each reaction well 1322 has a depth or height of approximately 1 millimeter (mm).
  • the reaction wells 1322 may have a shape such that the volume of each reaction well 1322 is or is approximately 25 mL when each reaction well 1322 has a depth or height of 1 mm.
  • the reaction wells 1322 contain dried enzymes and primers.
  • the primers and enzymes may be spotted into the reaction wells 1322 as liquids and dried (for example, in two spots per well).
  • the reaction wells 1322 may include dried primers and enzymes while the reagent blister 1340 may include the wet or liquid reagents.
  • the reagent blister 1340 and/or the reaction wells 1322 may contain liquid reagents and/or primers and enzymes, respectively, configured to allow for the testing of one or more of a viral target, a bacterial target, an antigen target, a parasite target, a microRNA target, an agricultural analyte, an enzyme, an environmental contaminant, pathogens, genomic materials, proteins, PSA levels, elevated or reduced cell counts, specific cells and/or cell types, infections and/or diseases associated with a particular industry or environment, infectious diseases, vector borne diseases, norovirus, rotavirus, and/or any other small molecules or biomarkers.
  • the dried enzymes and primers are contained in the reagent blister 1340 or elsewhere in the cartridge 1300 .
  • one or more heating elements in the analyzer 1400 are activated to increase a temperature of the mixture in the reaction wells 1322 and impedance sensors begin tracking data in real time.
  • the analyzer 1400 then conducts a test through an isothermal nucleic acid amplification process, and any results are communicated to an application and/or a database for further analysis.
  • each of the reader devices 110 , 600 , 910 , and 1400 may incorporate any of the functions and/or components of the other reader devices.
  • the components (and corresponding functions) of the reader device 600 in FIG. 6 may be integrated into the reader devices 110 , 910 , and 1400 .
  • each of the reader devices 110 , 600 , and 910 may include the functionality and features of the reader device 1400 .
  • the reader device 1400 may include in the functionality and features of the readers devices 110 and 910 to process any cartridge inserted into the reader device 1400 .
  • each of the cartridges 120 , 200 , 1000 , 1200 , and 1300 may incorporate any of the functions and/or components of the other cartridges.
  • the components and corresponding functions of the cartridge 1300 in FIGS. 13A-13E may be integrated into the cartridges 120 , 200 , 1000 , and 1200 .
  • the cartridge 1300 may include in the functionality and features of one or more of the cartridges 120 , 200 , 1000 , and 1200 and may be processed by any reader device described herein.
  • the various components of the handheld detection systems 100 and 900 may be integrated with an external computing device.
  • the external computing device for example a mobile phone, a computer, a tablet, a laptop, or similar device, may communicate with the reader devices 110 , 600 , 910 , and/or 1400 using a communication interface, for example the communications module 615 .
  • the external computing device may comprise a testing monitoring and/or control application installed thereon to provide a user options and abilities to monitor and/or control one or more of the cartridge and the reader device. Further details of the functionality of the testing control application (including providing a testing system user interface for controlling options and/or presenting test results and other test information to users, on a display of the remote device) are provided below with reference to FIGS. 15A-15P .
  • FIGS. 15A-15P depict screenshots of an example graphical user interface 1500 hosted on an external computing device and configured to provide testing control and/or monitoring of the handheld system disclosed herein.
  • the graphical user interface 1500 may include one or more of the features of the graphical user interface 800 described with reference to FIGS. 8A-8D above.
  • the user interface 1500 may be, for example, the user interface 620 illustrated in connection with the reader device 600 of FIG. 6 or the user interface 800 .
  • the user interface 1500 may be implemented with any of the reader devices 110 , 600 , 910 , and/or 1400 and/or assay cartridges 120 , 200 , 1000 , 1200 , and 1300 described herein.
  • the screens depicted in FIGS. 15A-15P may be displayed, for example, by an application executing on the external computing device paired to the reader device 110 , 600 , 910 , 1400 (e.g., by WiFi, Bluetooth, or the like).
  • the screens may allow a user of the external computing device to control and/or monitor the reader device 110 , 600 , 910 , 1400 from the external computing device.
  • FIG. 15A depicts an initial user screen 1505 which may be displayed when the application is activated or run.
  • a user selects the application from a home screen or the application is launched automatically when the external computing device is paired with the reader device.
  • the application may run in the background of the external computing device and automatically open or prompt the user when the application detects that the reader is paired to the external computing device or when a cartridge is inserted into the reader device.
  • the user screen 1505 optionally includes a header portion that may be generic to all or a majority of screenshots for the application.
  • the header portion may include a title portion and a menu portion.
  • the title portion may provide a title for the screen being viewed (for example, the title portion for the user screen 1505 includes “Who is Sick?”, prompting the user of the application to select or add a person for whom a test has been run, is being run, or will be run.
  • the menu portion optionally may comprise a “hamburger” button that, when clicked, presents the user with available options from a current screen (for example, the screen from which the user accesses the hamburger button.
  • the user screen 1505 allows the user to identify a patient for which test results are being generated by the reader device, test results are being reviewed, or a profile is being created, revised, or reviewed.
  • the user may be one of the patients identified on the screen 1505 or may be associated with one of the patients identified.
  • the user screen 1505 identifies a single patient's profile, “Benjamin Franklin”, but includes a button to add new patients or people to the application.
  • the user interface can link and reference tests associated with corresponding patients in a simplified and secure manner. Accessing a patient's account may require a password or biometric (or other) authentication to ensure privacy of test results and corresponding data.
  • the menu may provide the user with many options.
  • the options include: (1) closing the menu; (2) transitioning to a home page; (3) transitioning to a page to manage connected devices; (4) transitioning to a page for ordering supplies; (5) transitioning to a page with information about the application; (6) transitioning to a page to contact a vendor of the application; (7) transitioning to a page for a user manual; and (8) logging out of and exiting the application.
  • Option (1) may close the menu and return the user to the previously visible screen.
  • Option (2) may take the user to the home page of the application, which may be the “Who is Sick?” page where the patient is selected.
  • Option (6) may allow the user to contact the vendor of one or more of the application, the reader devices 110 , 600 , 910 , and/or 1400 , and the cartridges 120 , 200 , 1000 , 1200 , and/or 1300 .
  • Option (7) opens a digital user manual for one or more of the application, the reader devices 110 , 600 , 910 , and/or 1400 , and the cartridges 120 , 200 , 1000 , 1200 , and/or 1300 .
  • Option (8) causes the user to sign out (for example, de-authenticate) and exit the application.
  • Option (3) from the menu may transition the application to the user screen 1510 of FIG. 15B , having the title portion “Devices”.
  • the screen 1510 shows devices that are added to and/or associated with the application, such as the Reader #1 and the Reader #2, and an option to add a new device.
  • the application transitions to a pairing reader screen 1515 that requests the user to input information to enable the application to communicate with the new device(s), such as a new reader.
  • the pairing reader screen 1515 may prompt the user to pair the new reader with the application over Bluetooth, Wi-Fi, or another communication medium.
  • the pairing reader screen 151 may include a video prompt to show the user how to add the new reader and generally include instructions for pairing the new reader with the application.
  • the pairing reader screen 1515 may prompt the user to scan or enter a barcode on or associated with the new reader. Once the new reader is added to or associated with the application, the application may return to the screen 1510 , where the added reader (e.g., Reader #2) is shown with a note of “Device added!”.
  • the added reader e.g., Reader #2
  • the application transitions to a user screen 1520 of FIG. 15D .
  • the user screen 1520 may provide various information and options to the user. For example, the user screen 1520 provides an option to change the name of the Reader #1, to forget the Reader #1, and to connect to the Reader #1. If the Reader #1 is currently connected to the application, then the user screen 1520 may provide an option to disconnect from the Reader #1.
  • the user screen 1520 also displays identifying information for the Reader #1 and may include a connection status indicator, indicating a status of the connection between the Reader #1 and the application. In some embodiments, the user screen 1520 also includes information regarding current status of the Reader #1.
  • the reader devices and the cartridges provide testing for target agents.
  • the application on the external computing device may facilitate the performance, control, and review of the test and the review and/or communication of the test results.
  • user screen 1525 of FIG. 15E shows results for the user Benjamin Franklin for two previous tests or provides the user the option to start a new test.
  • the screen 1525 shows the two previous test results: a positive test result for Influenza A/B on Apr. 28, 2019 and a negative test result for Influenza A/B on Apr. 28, 2019.
  • the user of the external computing device may select one of the previously completed positive and negative test results and review details of the test, the test results, and any symptoms reported for the patient at the time that the selected test was performed.
  • the user can review identifiers for the cartridge from each test and/or the reader device from each test.
  • the user interface 1500 may prompt the user to connect to a reader device (for example, one of reader devices 110 , 600 , 910 , and/or 1400 , if not already connected).
  • the user interface may also request the user to identify a cartridge (for example, one of cartridges 120 , 200 , 1000 , 1200 , and/or 1300 ) to be used in the test.
  • an influenza test uses a first cartridge while a bronchitis test uses a second cartridge.
  • identifying the cartridge to being used for the test may be essential to the test providing a reliable result when analyzed by the reader device.
  • the reader device may receive specific instructions and/or set points, etc., for use in the test based on the identified cartridge.
  • the instructions provided by the screen 1530 may include scanning a barcode or taking a picture of the cartridge being used or manually entering information identifying the cartridge.
  • the click may be the result of a mechanical coupling of the reader device to the cartridge.
  • the user interface 1500 may provide additional instructions to the user.
  • the screens 1540 - 1550 also include navigation buttons to navigate between screens.
  • the screen 1550 may indicate to the user that the corresponding test has begun. Specifically, the screen 1550 provides the user with a summary of the patient or subject (for example, Benjamin Franklin) along with some information about the patient (for example, date of birth).
  • the screen 1550 also provides details on the test being run, here the Influenza A/B test, and an identifier for the cartridge being used to run the test and the reader running the test.
  • the screen 1550 also includes a timer or countdown indicating how much time is remaining in the current test, if any.
  • the user interface 1500 may track and/or display information from when the reader device was last connected to the user interface 1500 and the external computing device. Selecting the new test on the screen 1570 causes the user interface 1500 to present the screen 1575 of FIG. 15O , which includes details of the positive influenza A/B test, symptoms reported along with the test by the user, and details of the cartridge used in the test and potentially the reader device used in the test.
  • the screen 1575 of FIG. 15O may also include an indicator (not shown in the figures) of a diagnosed ailment and/or one or more recommended steps to follow-up on the test results and/or the indicated ailment. Screen 1580 of FIG.
  • 15P provides the user with options for sharing the test results, for example via text message, e-mail, printing, and so forth.
  • the user establishes a default sharing plan for all test results, symptoms, and other data for a particular patient. For example, the user can set up the sharing plan to e-mail or message all results, symptoms, and other data to the patient's doctor or parents automatically upon completion of a test or entry of new data, or both.
  • the external computing device and the user interface 1500 are used to scan a cartridge identifier (e.g., cartridge identifier 215 of FIG. 2B ) of a cartridge before inserting the cartridge into the reader device.
  • a cartridge identifier e.g., cartridge identifier 215 of FIG. 2B
  • the paired reader device detects the inserted cartridge and sends a message to the user interface that the cartridge has been inserted.
  • the user interface 1500 may then display one of the screens described above, with reference to FIGS. 15A-15P .
  • one or more of the screens of the FIGS. 15A-15P include one or more of the indications, buttons, input fields, areas, and so forth of the FIGS. 8A-8D .
  • the user interface may receive symptoms that the patient is experiencing and combine these symptoms with the test results from the reader device to determine whether the patient is suffering from an illness or ailment corresponding to the target agent. For example, if the test result from the reader device indicates the presence of the influenza A/B virus in the patient's mucus but the patient is not experiencing or reporting any symptoms, then the user interface may determine that the patient is not suffering from the influenza virus but is instead a carrier for the virus. On the other hand, when the test result indicates the presence of the influenza A/B virus and the patient reports symptoms known to coincide with the influenza A/B virus in someone suffering from the influenza illness, then the user interface may determine that the patient is infected with the influenza illness.
  • a standard setting or national organization such as the Center for Disease Control (CDC) or similar organization or entity, may establish the one or more metrics.
  • the user interface may use the test results from the reader device and the symptom information provided by the user to determine whether the patient is (1) ill or sick or (2) a carrier for the target agent.
  • the user interface offloads one or more of the determinations described herein to one or more external systems with which the user interface (and the corresponding external computing device) interacts.
  • the reader device may provide test results that include a range of values, where the range of values correspond to a range of possible detection levels of the target agent.
  • the test results may include one or more of a likelihood that the mucus sample included the target agent (for example, between 0 and 100% probability) and a quantity of the target agent determined to have been included in the mucus sample.
  • the probability that the mucus sample included the target agent may be associated with the quantity of the target agent determined to have been included in the mucus.
  • the range of possible detection levels may refer to different likelihoods or probabilities that the patient has a particular virus or infection.
  • the score (or probability) may be assigned a minimum value, for example 50 out of a 0 to 100 range. Then, if the patient is experiencing any symptoms associated with the illness associated with the virus or infection, then the value of the score (indicating that the patient is suffering from the corresponding illness) may be increased. For example, for each symptom that the patient experiences that is associated with the illness, the value may increase by a threshold value (for example, 10 points). Thus, the combination of the target agent detection and the symptoms can increase or decrease the score or probability of the patient being sick.
  • the score may be assigned a different minimum value, for example 25 out of the 0 to 100 range. Accordingly, when the test results indicate a lower probability of the presence of the target agent, more symptoms suffered by the patient are needed to increase the score to the same value as compared to when the test results indicate a high probability of sickness. If the reader device indicates that the patient does not have the virus or infection (or that a quantity of the target agent below the second threshold was present), then the score may be assigned a zero value, for example 0 out of the 0 to 100 range.
  • the user interface and the reader device may together generate the score that represents the probability of the patient being sick based on the test results of the target agent and the symptoms suffered by the patient.
  • the user interface may review the test results and the provided symptoms to determine whether the patient is suffering from a particular illness not associated with the target agent for which the test was run. For example, if the patient's test results are negative for influenza A/B but the patient is experiencing a fever with chills and a sore throat, the user interface may determine that the patient is suffering from a cold or respiratory syncytial virus (RSV).
  • RSV respiratory syncytial virus
  • the user interface may identify an illness that the patient is suffering from or is likely suffering from based on a positive or negative test results and the symptoms experienced.
  • the user interface may use knowledge (for example, databases) of similarities and differences in symptoms of different illnesses but differences in test results and so forth in illness determinations.
  • the user interface generates a score value that indicates a probability that the patient is sick or ill, based on the test results and the symptom information.
  • the user interface may further aggregate external information into the score value, regardless of what the test results and symptoms by themselves would otherwise indicate.
  • the external information may include one or more of test results from other patients that used the same reader device, test results from other reader devices that interfaced with the user interface and the external computing device, test results and other diagnostic information for patients in a hospital or a geographic region, and so forth.
  • the user interface may use test results and/or symptom information from other patients tested by the reader device to inform further the score values.
  • the user interface may use this information to increase a score or probability that the patient is ill or sick, even if the patient's test results and/or symptoms may alone not indicate that the patient is ill.
  • the test results and the symptom information for the patient may indicate that the patient is ill but other patients having similar test results and symptoms report that they are not ill.
  • the user interface then may decrease the score or probability that the patient is ill, regardless of what the patient's test results and/or symptom information otherwise indicate.
  • the user interface may increase the score or probability that the patient is sick.
  • the user interface may decrease the score or probability that the patient is sick, regardless of the test results and symptoms.
  • the user interface performs one or more actions based on the score or probability values.
  • the user interface may communicate information to one or more of the user, the patient, attending medical staff, the CDC, or similar entities.
  • the user interface may generate an alert to the one or more of the user, the patient, attending medical personnel, the CDC, or similar entities.
  • the alert may comprise one or more of a phone call, a text message, an e-mail message, a push message, an audio message, a flashing indicator, or audible indicator, or any other communication used to communicate information.
  • the user interface may automatically generate and transmit an alert to the user based on the results of the test or the indicated symptoms, a combination of the two, or the test results or symptoms in aggregate with information from other patients. For example, if the test results and the indicated symptoms suggest that the patient is suffering from a rare illness, then the user interface may generate and communicate an alert to the patient or user suggesting a follow-up visit to a specialist. Similarly, if the test results and the indicated symptoms suggest that the patient is suffering from highly contagious illness, then the user interface may generate and communicate the alert to the patient or user requesting that the patient restrict interaction with others to minimize risk of communication of the illness to others.
  • the user interface may generate and communicate the alert to the patient or user but also to local, regional, or national medical staff or disease monitoring agencies.
  • the reader device, cartridge, and user interface on the external computing device may generate information used to help detect an outbreak of a virus or disease.
  • the user interface and the external computing device may communicate and/or interact with a system that tracks illnesses over a geographic area, for example a city, county, state, or nation, or a specific portion of the population.
  • the user interface and the external computing device may enable tracking of diseases and/or infections by the system for a number of patients in various geographic areas.
  • the system performs the tracking based on one or both of the test results and the identified symptoms.
  • the system performs the tracking based on the scores or probabilities generated by the user interface.
  • the system may aggregate and use the information from multiple user interfaces and external computing devices to generate a geographic heat map.
  • the heat map may show levels of one or more illnesses and/or corresponding rates of infection or healing as different colors or levels on the map, where different colors correspond to different levels (for example, numbers) of reported injections or rates of infection. Thus, the heat map may visually show how numbers of ill patients vary in the geographic area.
  • the system may use such heat maps to identify pockets of specific illnesses or infections and/or an epidemic that is occurring based on aggregated test results and symptoms provided from multiple user interfaces and corresponding external computing devices.
  • the heat map may show different quantities of illnesses or different rates of illness detection in different colors.
  • the heat map may enable an entity to review quickly the geographic area to identify relational information (for example, information for portions of the geographic area relative to one another) and specific information (for example, detailed information for individual portions of the geographic area).
  • the user interface and the external computing device may be integrated with a system (for example, the system that generates the heat map) used to track and/or determine need for vaccines or other medications.
  • the system may receive the test results, symptoms, and/or scores from a number of user interfaces and corresponding external computing devices.
  • the system may track that information to ensure that a particular geographic region is supplied with appropriate vaccines or medications to handle the identified quantity of illnesses. If the system identifies that a difference in identified illnesses and an expected level of supplies exceeds a determined threshold, then the system may automatically request vaccine and/or medication suppliers to increase production to meet an expected demand based on the illnesses tracked by the system.
  • the system determines that test results, symptoms, and/or scores received from a city in California indicate that 50,000 people out of a population of 500,000 are suffering from influenza A/B.
  • the city is expected to have vaccine and medication supplies for 10,000 people to treat and prevent the spread of the influenza A/B virus (for example, only 10,000 units of medication and/or vaccines).
  • the system may determine that the difference of 40,000 people exceeds the threshold amount and may automatically request that influenza A/B vaccine and medication manufacturers and/or suppliers increase production and provide an increased supply to the city.
  • Such automatic detection of supply need and request for additional supplies may improve response times in times of outbreaks and help prevent and/or reduce the spread of communicable diseases.
  • Such aggregate tracking of test results, symptoms, and/or scores may allow the system to provide recommendations.
  • recommendations may include increased education, advertisement, and so forth.
  • the system may recommend increased education of the different diseases and advertisements to inform people of the potential confusion and to help them seek treatment.
  • certain sexually transmitted diseases may exhibit cold- or flu-like symptoms.
  • hepatitis and/or gonorrhea may have similar symptoms to the common cold or influenza.
  • some people experiencing the cold-like or flu-like symptoms may not get tested for any infection, assuming they just have the cold or flu.
  • the system may determine that an unusually large number of people in a town have test results, symptoms, and scores that indicate infection with hepatitis during a period when a large number of patients are reporting cold or flu infections. The system may then determine that education regarding safer sex practices and differences between the diseases should be provided to the town. The system may also recommend increased advertisement about the spike in infections to encourage the safer practices and lead to increased detection and treatment for the appropriate illness.
  • the user interface may also generate an indicator to indicate whether the patient is becoming sicker or healthier. For example, if the user performs multiple tests for the patient, then the user interface may determine that different combinations of symptoms suffered by the patient or different quantities of the target agent in the test sample indicate whether the patient is sicker than a previous test or healthier than a previous test.
  • the indicator may comprise an arrow or representation of a face, or similar indicator.
  • Some embodiments of the methods, systems and compositions provided herein include devices comprising an excitation electrode and a sensor electrode.
  • the excitation electrode and the sensor electrode measure electrical properties of a sample.
  • the electrical properties comprise complex admittance, impedance, conductivity, resistivity, resistance, and/or a dielectric constant.
  • the electrical properties are measured on a sample having electrical properties that do not change during the measurement. In some embodiments, the electrical properties are measured on a sample having dynamic electrical properties. In some such embodiments, the dynamic electrical properties are measured in real-time.
  • an excitation signal is applied to the excitation electrode.
  • the excitation signal can include direct current or voltage, and/or alternating current or voltage.
  • the excitation signal is capacitively coupled to/through a sample.
  • the excitation electrode and/or the sensor electrode is passivated to prevent direct contact between the sample and the electrode.
  • parameters is optimized for the electric properties of a sample.
  • parameters can include the applied voltage, applied frequency, and/or electrode configuration with respect to the sample volume size and/or geometry.
  • the voltage and the frequency of the excitation voltage may be fixed or varied during the measurement. For example, measurement may involve sweeping voltages and frequencies during detection, or selecting a specific voltage and frequency which may be optimized for each sample.
  • the excitation voltage induces a current on the signal electrode that is can vary with the admittance of the device and/or sample characteristics.
  • the detection parameters is optimized by modeling the admittance, device and sample by the lumped-parameter equivalent circuit consisting of electrode-sample coupling impedances, sample impedance, and inter-electrode parasitic impedance. Parameters of the lumped-parameter equivalent circuit is determined by measuring the admittance of the electrode-sample system at one or many excitation frequencies for a device. In some embodiments, the complex (number having both real and imaginary components) admittance of the electrode-sample system is measured using both magnitude- and phase-sensitive detection techniques. In some embodiments, the detection parameters are optimized by determining the frequencies corresponding to the transitions between the frequency regions by measuring the admittance across a wide range of frequencies. In some embodiments, the detection parameters are optimized by determining the frequencies corresponding to the transitions between the frequency regions by computing from the values given lumped-parameter model.
  • the admittance of a capacitively-coupled electrode-sample system comprises three frequency regions: a low frequency region dominated by the electrode-sample coupling impedance, a mid-frequency region dominated by the sample impedance, and a high frequency region dominated by parasitic inter-electrode impedance.
  • the admittance in the electrode-sample coupling region is capacitive in nature and is characterized by a magnitude that increases linearly with frequency, whose phase is ninety degrees.
  • the admittance in the sample region is conductive in nature and is characterized by an admittance that does not vary significantly with respect to frequency, whose phase is approximately zero degrees.
  • the admittance inter-electrode region is capacitive in nature and is characterized by a magnitude that increases linearly with frequency and a phase of ninety degrees.
  • an induced current at the pick-up electrode is related to the excitation voltage and complex admittance by the relation:
  • the device measures both the excitation voltage magnitude and induced current magnitude to determine the magnitude of the complex admittance. In some embodiments, the device is calibrated to known excitation voltages and measure the magnitude of the induced current. In order to determine the phase of complex admittance, the device may measure the relative phase difference between the excitation voltage and the induced current.
  • the magnitude and phase is measured directly.
  • the magnitude and phase is measured indirectly e.g., by using both synchronous and asynchronous detection.
  • the synchronous detector gives the in-phase component of the induced current.
  • the asynchronous detector gives the quadrature component of the induced current. Both components can be combined to determine the complex admittance.
  • a machine such as a general purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein.
  • DSP digital signal processor
  • ASIC application specific integrated circuit
  • FPGA field programmable gate array
  • a general purpose processor can be a microprocessor, but in the alternative, the processor can be a controller, microcontroller, combinations of the same, or the like.
  • a processor can also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration. Although described herein primarily with respect to digital technology, a processor may also include primarily analog components. For example, any of the signal processing algorithms described herein may be implemented in analog circuitry.
  • a computing environment can include any type of computer system, including, but not limited to, a computer system based on a microprocessor, a mainframe computer, a digital signal processor, a portable computing device, a personal organizer, a device controller, and a computational engine within an appliance, to name a few.
  • the methods disclosed herein comprise one or more steps or actions for achieving the described method.
  • the method steps and/or actions may be interchanged with one another without departing from the scope of the claims.
  • the order and/or use of specific steps and/or actions may be modified without departing from the scope of the claims.
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EP3899022A4 (fr) 2023-03-01
WO2020132008A1 (fr) 2020-06-25
CA3124120A1 (fr) 2020-06-25

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